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. 2019 Dec 2;132(23):jcs232850. doi: 10.1242/jcs.232850

ER-associated degradation in health and disease – from substrate to organism

Asmita Bhattacharya 1,2, Ling Qi 1,3,*
PMCID: PMC6918741  PMID: 31792042

ABSTRACT

The recent literature has revolutionized our view on the vital importance of endoplasmic reticulum (ER)-associated degradation (ERAD) in health and disease. Suppressor/enhancer of Lin-12-like (Sel1L)–HMG-coA reductase degradation protein 1 (Hrd1)-mediated ERAD has emerged as a crucial determinant of normal physiology and as a sentinel against disease pathogenesis in the body, in a largely substrate- and cell type-specific manner. In this Review, we highlight three features of ERAD, constitutive versus inducible ERAD, quality versus quantity control of ERAD and ERAD-mediated regulation of nuclear gene transcription, through which ERAD exerts a profound impact on a number of physiological processes.

KEY WORDS: Sel1L-Hrd1 ERAD; Health; Disease; Constitutive ERAD; Inducible ERAD; ERAD substrate, Quality control; Quantity control; Nuclear gene transcription

Summary: This Review highlights recent findings that have revolutionized our view on the vital importance of endoplasmic reticulum (ER)-associated degradation (ERAD) in health and disease.

Introduction

Secreted proteins, such as hormones and growth factors, as well as transmembrane receptors, critically regulate nearly all aspects of life, including food intake, water balance, growth, metabolism and immunity. The endoplasmic reticulum (ER) is a specialized cellular compartment where the folding and maturation of most of these proteins take place (Hegde and Lingappa, 1997). Aberrations in these complex thermodynamic folding processes and kinetic parameters can disrupt cellular homeostasis and lead to debilitating diseases, such as liver and lung diseases, and diabetes (Braakman and Bulleid, 2011; Wiseman et al., 2007). ER-associated degradation (ERAD) is a highly conserved, major regulatory system that guards against such events, thereby maintaining proteostasis within the ER (Aridor and Balch, 1999; Guerriero and Brodsky, 2012). Despite being well-characterized at the biochemical level, which has been reviewed extensively elsewhere (Christianson and Ye, 2014; Merulla et al., 2013; Olzmann et al., 2013), the significance of ERAD on a systemic (patho)physiological scale has, until recently, remained unknown (Hwang and Qi, 2018; Qi et al., 2017). This Review discusses the emerging roles of ERAD in health and disease, without which, our understanding of pathogenesis of a large number of diseases remains incomplete.

The suppressor/enhancer of lin-12-like (Sel1L)–HMG-coA reductase degradation protein 1 (Hrd1) protein complex (Fig. 1A; note Sel1L is also known as Hrd3, and Hrd1 as SYVN1) – the focus of this Review – is central to the most-conserved and best-characterized branch of mammalian ERAD (Mueller et al., 2008, 2006; Ye et al., 2004). The ERAD process begins with the selection of the substrate protein; this is based on either glycosylation tags, mannose trimming status and/or conformational change, and is aided by chaperones, such as 78-kDa glucose-regulated protein (Grp78; also known as HSPA5), ER degradation-enhancing α-mannosidase-like protein (Edem) family proteins and osteosarcoma amplified 9 (Os9) (Araki and Nagata, 2011; Bernasconi et al., 2010; Christianson et al., 2008; Hegde and Ploegh, 2010; Olzmann et al., 2013; Smith et al., 2011; van der Goot et al., 2018). In a second step, the substrate is retro-translocated into the cytosol through the polytopic dislocon Hrd1; Hrd1 itself forms a ubiquitin-gated channel activated by auto-ubiquitylation (Baldridge and Rapoport, 2016; Carvalho et al., 2010; Christianson et al., 2012). Other potential dislocon proteins, such as degradation in endoplasmic reticulum protein (Derlin) family members – Derlin-1, Derlin-2 or Derlin-3 – have been identified as possibly working together with Hrd1, but their role needs further characterization in mammalian systems (Lilley and Ploegh, 2004; Ye et al., 2004). The adaptor protein Sel1L is indispensable for the stability and function of Hrd1 (Mueller et al., 2008, 2006; Sun et al., 2014; Vashistha et al., 2016). Subsequent to the retro-translocation, substrates are ubiquitylated by Hrd1 (Kikkert et al., 2004) and targeted for proteasomal degradation by the ATPase valosin-containing protein Vcp (also known as p97) and other ubiquitin-modifying enzymes (Ernst et al., 2009; Meyer et al., 2012) (Fig. 1A). In addition, other E3 ligases, such as glycoprotein 78 (Gp78, also known as AMFR), membrane-associated ring-CH-type finger 6 (March6), ring finger protein 5 (Rnf5, also known as Rma1) and tripartite motif containing 13 (Trim13), may work either in parallel or together with Hrd1; however, these systems remain poorly characterized (Altier et al., 2011; Fang et al., 2001; Hassink et al., 2005; Younger et al., 2006; Zhang et al., 2015) and will not be discussed here. Biochemical studies have identified some proteins as possible ERAD substrates in mammalian cell lines, such as mutant α-antitrypsin, mutant transthyretin, cystic fibrosis transmembrane conductance regulator (CFTR) and unassembled Cd147 (also known as BSG) (Christianson et al., 2012; Christianson et al., 2008; Liu et al., 1997; Sifers et al., 1988; Tyler et al., 2012; Ward et al., 1995); however, whether or not these proteins are bona fide endogenous ERAD substrates remains to be verified in vivo.

Fig. 1.

Fig. 1.

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Overview over physiological ERAD and emerging paradigms. (A) Sel1L–Hrd1-mediated ERAD. ERAD is a highly conserved cellular system that is responsible for the retrotranslocation of substrate proteins from the ER to the cytosol for proteasomal degradation. This process starts with substrate recruitment by chaperones (Grp78, Os9, Xtp3b, Edem1–Edem3) and adaptor proteins (Sel1L, Derlin proteins), followed by their retrotranslocation through the dislocon channel (Hrd1 or Derlin), and ubiquitylation by an E3 ligase (Hrd1) and ATPase (Vcp), before degradation at the proteasome. (B–D) Recent in vivo studies have highlighted three major conceptual advances in mammalian ERAD biology. (B) Constitutive versus inducible ERAD. ERAD may function in a constitutive capacity to maintain optimal levels of key proteins regulating critical physiological process such as food intake, water and energy balance, and B cell development, or in an inducible capacity, whereby ERAD gene expression is triggered by drug-induced UPR. (C) Quality versus quantity control by ERAD. Physiological ERAD has been reported to perform both quality control of misfolded substrates, thus ensuring fidelity of production and protecting against their aggregation and loss-of-function effects, and quantity control of folding-competent substrates, thereby regulating their abundance and guarding against over-activation and gain-of-function effects. (D) ERAD-regulated transcription. ERAD influences gene expression in the nucleus through the direct manipulation of ER-related transcription factors; for example, the Ire1α–Xbp1s axis of UPR, and the Crebh–Fgf21 axis in metabolism and growth. Direct degradation of nuclear transcription factors by ERAD is not shown here. Tg, thapsigargin; Tm, tunicamycin; proINS, proinsulin; uXBP1, unspliced XBP1; S1P and S2P, Golgi site-specific proteases.

Deletion of any key component of ERAD, such as Sel1L, Hrd1, Derlin or Vcp, results in embryonic lethality in mice (Dougan et al., 2011; Eura et al., 2012; Francisco et al., 2010; Müller et al., 2007), underscoring the physiological significance of ERAD in development. Recently, cell type-specific knockout mice of specific ERAD genes have been reported, revealing that ERAD is linked to a plethora of physiological conditions, often in a substrate-specific manner (Qi et al., 2017). These findings have allowed us to map out the stipulations that are necessary for the identification of a bona fide ERAD substrate in vivo (Box 1), and significantly changed our view of the physiological and pathological importance of ERAD. In this Review, we highlight the hallmark features obtained from these recent animal studies: constitutive versus inducible ERAD, quality versus quantity control by ERAD, and ERAD-mediated regulation of gene transcription (Fig. 1). These characteristics enable ERAD to function in a basal capacity regulating key physiological processes in the body, ensure both fidelity and abundance of ER protein production, and communicate external cues to gene expression in the nucleus.

Box 1. How to identify a bona fide endogenous ERAD substrate.

Hallmarks that are required for a protein to be classed as an ERAD substrate are that there is: (1) a stabilization of substrate protein (elongation of half-life) in the absence of ERAD; (2) a significant increase in substrate protein levels in the absence of ERAD; (3) no significant upregulation of substrate mRNA levels; (4) E3 ligase-dependent poly-ubiquitylation of the substrate is seen; (5) localization of substrate protein in the ER during at least some part of its maturation; (6) interaction with core ERAD components (E3 ligase or adaptor protein).

Constitutive versus inducible ERAD

Accumulation of misfolded proteins triggers the ‘unfolded protein response’ (UPR), which acts to reduce ER load and increase the expression of ER chaperones and ERAD components (Ron and Walter, 2007; Walter and Ron, 2011). This ‘UPR-centric’ mechanism of stress response and ERAD induction and/or function is thought to occur via inositol-requiring enzyme 1α (Ire1α)- or activating transcription factor 6 (Atf6)-mediated transcriptional control of ERAD gene expression (such as genes encoding Hrd1, Sel1L, Edem or Derlin), and is largely based on studies that used chemical agents, which cause massive ER stress (Hampton, 2000; Zhang et al., 2011). However, whether or not such scenarios apply in vivo under physiological conditions (where ER stress is likely to be very mild, if present at all, in many cell types) remains to be determined.

Several recent studies using animal models have suggested that ERAD mediated by Sel1L–Hrd1 plays a critical constitutive role within the cell (Fig. 1B). Indeed, ERAD genes are constitutively and ubiquitously expressed, and are also active, independently of any UPR activation. This constitutive ERAD degrades substrate proteins, which may be misfolded or even folding or maturation competent, to not only ensure fidelity of production, but to also regulate the abundance of the substrate.

Recent publications by our group and others have independently shown that Sel1L–Hrd1-mediated ERAD is constitutively active in the murine liver under basal conditions (with very mild, if any, UPR) (Bhattacharya et al., 2018; Wei et al., 2018a). Sel1L–Hrd1 expression in hepatocytes increases with age or feeding. This constitutive ERAD function in mice fed with regular chow diet is instrumental in regulating the abundance of its substrate cAMP-responsive element-binding protein, hepatocyte specific (Crebh; also known as CREB3L3), an ER-resident transcription factor, which in turn induces fibroblast growth factor 21 (Fgf21), a powerful metabolic hormone (Bhattacharya et al., 2018; Wei et al., 2018a). In the absence of this constitutive ERAD in the liver, mice exhibit growth retardation with significantly altered systemic energy homeostasis – largely owing to the over-activation of the Crebh–Fgf21 axis (Bhattacharya et al., 2018; Wei et al., 2018a).

Other examples of constitutive ERAD are the Sel1L–Hrd1-mediated degradation of the UPR sensor protein Ire1α (Sun et al., 2015) and the pre-B cell receptor protein (pre-BCR) (Ji et al., 2016; Yang et al., 2018). The first study demonstrated that Ire1α is an endogenous substrate of Sel1L–Hrd1-mediated ERAD (Sun et al., 2015). Here, the degradation of Ire1α by Sel1L–Hrd1 (with the help of the ER chaperones Os9 and Grp78) occurs constitutively to restrain Ire1α activity under basal physiological conditions in many cell types. In the gut epithelium, ERAD-mediated regulation of Ire1α activity protects the intestines from inflammatory disease (Sun et al., 2016, 2015). Similarly, two independent studies have shown that in developing B cells, Sel1L–Hrd1-mediated ERAD constitutively controls the abundance of surface pre-BCR, thereby restraining its signaling during the transition from large to small pre-B cell stage (Ji et al., 2016; Yang et al., 2018).

Moreover, in neurons expressing the antidiuretic hormone arginine vasopressin (Avp), Sel1L–Hrd1-mediated ERAD constitutively acts to maintain systemic water balance by clearing misfolded wild-type Avp prohormone (proAvp) proteins from the ER (Shi et al., 2017). Accordingly, deletion of Sel1L in Avp neurons under basal conditions causes diabetes insipidus with diluted urine and low urine osmolality. Constitutive ERAD activity towards misfolded nascent wild-type proAvp protein is a key step in proAvp maturation to ensure its exit from the ER (Shi et al., 2017). ProAvp protein contains 16 cysteine residues with eight disulfide bonds and is thus likely prone to misfolding. Indeed, many mutations that cause the retention of nascent proAvp proteins in the ER have been identified in humans with diabetes insipidus (Birk et al., 2009; Ito et al., 1997, 1999; Phillips, 2003; Rittig et al., 1996), although the link between ERAD and these pathogenic mutants remains unknown.

Similarly, in hypothalamic pro-opiomelanocortin (Pomc)-expressing neurons, constitutive ERAD functions to oversee the maturation of nascent Pomc in the ER (Kim et al., 2018). Pomc is a metabolic prohormone with two disulfide bonds, which produces derivatives that regulate key physiological processes including food intake and post-feeding satiety. Pomc neuron-specific deficiency of Sel1L in mice causes them to be hyperphagic and become obese at three to four months of age on a normal chow diet. Mechanistically, Sel1L deletion in Pomc neurons leads to the accumulation of misfolded wild-type Pomc protein, which, in a dominant-negative fashion, retains otherwise folded wild-type Pomc protein in the ER (Kim et al., 2018).

These studies collectively demonstrate the importance of constitutive ERAD in controlling the maturation and abundance of specific ER proteins, thereby fine-tuning their activities within the cell (Fig. 1B). This constitutive function of ERAD is likely to be independent of the UPR and is sufficient to ensure ER proteostasis in certain cell types under (patho-)physiological conditions. This process exerts a key homeostatic control of basic physiological processes in a substrate-specific manner, including, but not limited to, food intake, water balance, systemic energy homeostasis and cellular development.

To further elaborate this point, we have compared the phenotypes of animal models that are deficient in either ERAD or UPR published to date to assess the relative contribution of UPR and ERAD in various cell types (Table 1). As an example, unlike Pomc neuron-specific Sel1L-deficient mice, which show early-onset obesity with a normal chow diet (Kim et al., 2018), Pomc neuron-specific Ire1α-deficient mice exhibit no significant phenotype on a normal chow diet (Xiao et al., 2016; Yao et al., 2017). Only when placed on a high-fat diet for an extended period of time, were Ire1α-deficient mice found in one study to become obese (Yao et al., 2017), but this observation was not recapitulated in another study (Xiao et al., 2016), possibly in part due to different Ire1α floxed mouse models used in these two studies. Therefore, we can conclude that UPR- and ERAD-deficient mouse models exhibit distinct phenotypes in most, if not all, cases (Table 1), suggesting that these two processes may exert disparate effects in vivo. Additionally, in several instances, ERAD-deficient models showcased more severe phenotypes than the corresponding UPR-deficient models (Table 1), suggesting that constitutive ERAD may actually play a more pertinent role than UPR in these cell types in the context of normal physiology.

Table 1.

Comparison between cell type-specific mouse models that are deficient in either ERAD or UPR

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Quality versus quantity control by ERAD

Classically, ERAD has largely been associated with quality control, that is, the clearance of ‘misfolded’ proteins in the ER (Christianson and Ye, 2014; Ye et al., 2004). Recent work using Avp and Pomc neuron-specific Sel1L-knockout mice and cells has delineated that Sel1L–Hrd1-mediated ERAD is responsible for the quality control of the prohormone maturation process in neuroendocrine cells (Fig. 1C). As described above, in the absence of Sel1L, aberrantly folded Pomc or proAvp molecules accumulate and abrogate the maturation of their otherwise properly folded counterparts by engaging them in aggregate formation in a dominant-negative manner (Table 2). Interestingly, neither of these Pomc- or Avp-specific Sel1L-knockout mouse models show any overt signs of neuronal death, inflammation or ER stress (Kim et al., 2018; Shi et al., 2017), consistent with the notion that protein aggregates in the ER are less toxic (than cytosolic aggregates) and can be well tolerated by the cell (Vincenz-Donnelly et al., 2018).

Table 2.

Overview over endogenous ERAD substrates and their localization and pathology

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Similarly, Sel1L deficiency in adipocytes leads to their faulty maturation, and subsequent aggregation of lipoprotein lipase (Lpl) in the ER (Sha et al., 2014a). Accordingly, adipocyte-specific Sel1L-knockout mice exhibit postprandial hypertriglyceridemia and are resistant to diet-induced obesity. In Schwann cells, deletion of Derlin-2 results in ER retention of misfolded myelin protein zero (P0, also known as MPZ), leading to defective myelin morphology and function, and increased propensity to Charcot–Marie–Tooth 1B (CMT1B) neuropathy (Volpi et al., 2019). Moreover, deletion of Sel1L in pancreatic β-cells leads to impaired proinsulin maturation in the ER, glucose-stimulated insulin secretion and mild hyperglycemia in mice (Hu et al., 2019). However, fully understanding the relevance and importance of Sel1L–Hrd1 ERAD in β-cell biology and proinsulin maturation requires further studies. These examples of ERAD-mediated quality control demonstrate the significance of substrate-specific ERAD in physiology.

Recent studies suggest that ERAD may also work in a capacity that controls the quantity of proteins by degrading folding-competent proteins (e.g. Crebh, Ire1α and pre-BCR), and thereby optimizing their associated downstream processes (Fig. 1C). In the absence of ERAD, these substrate proteins accumulate, which ultimately leads to gain-of-function phenotypes (Table 2). Although quantity control by ERAD has been demonstrated in the past in the context of HMG-coA reductase (Hmgcr) degradation in yeast and mammalian cells in vitro (Foresti et al., 2013; Hegde and Ploegh, 2010; Johnson and DeBose-Boyd, 2018), in vivo evidence remains limited. Indeed, accounts from animal models depicting Hmgcr degradation through Gp78-mediated ERAD in the context of hepatic cholesterol production remain controversial, as one study demonstrated Hmgcr to be a substrate of Gp78 (Liu et al., 2012), whereas another negated it (Tsai et al., 2012).

By using proteomic and biochemical approaches in the liver, we and others have shown that Sel1L-Hrd1 ERAD is able to recruit and ubiquitylate Crebh for proteasomal degradation (Bhattacharya et al., 2018; Wei et al., 2018a). In Sel1L- and Hrd1-deficient hepatocytes, Crebh accumulates in the hepatic ER and, following proteolysis at the Golgi, its N-terminal domain, which encodes an active transcription factor, translocates to the nucleus where it induces the expression of Fgf21. Consequently, these mice phenocopy mouse models with gain-of-function of Fgf21 in exhibiting growth retardation, lower serum lipid levels, increased insulin sensitivity (Inagaki et al., 2007; Inagaki et al., 2008; Kharitonenkov et al., 2005; Owen et al., 2014), reduced female fertility (Owen et al., 2013), adipose tissue browning (BonDurant et al., 2017; Fisher et al., 2012; Hondares et al., 2010; Owen et al., 2014), and resistance to diet-induced obesity (Kharitonenkov et al., 2005). In addition, Hrd1 also degrades certain metabolic enzymes in hepatocytes, such as ectonucleoside triphosphate diphosphohydrolase 5 (Entpd5) in the ER, carnitine palmitoyltransferase 2 (Cpt2) and required for meiotic nuclear division 1 homolog (Rmnd1) in mitochondria, and hydroxysteroid 17-β dehydrogenase 4 (Hsd17b4) in peroxisomes (Wei et al., 2018b); this may also contribute to the phenotype of hepatocyte-specific ERAD-deficient mice.

Similarly, in many cell types, including intestinal epithelium, adipocytes and pancreas, Sel1L–Hrd1-mediated ERAD regulates the quantity of the UPR-sensor Ire1α, as deletion of either Sel1L or Hrd1 leads to the accumulation and mild activation of Ire1α (Sun et al., 2015). Furthermore, a more-recent study reported the identification of a Hrd1–axin interactor, dorsalization-associated (Aida) ERAD complex, which ubiquitylates and degrades key triglyceride synthesis enzymes, including glycerol-3-phosphate acyltransferase 3 (Gpat3), monoacylglycerol o-acyltransferase 2 (Mogat2) and diacylglycerol o-acyltransferase 2 (Dgat2), in enterocytes (Luo et al., 2018). The authors showed that these degradation events protect mice from excessive lipid absorption, postprandial hypertriglyceridemia and obesity (Luo et al., 2018). However, the relevance and importance of Aida for the function of Hrd1 remains to be established.

In the immune system, Sel1L–Hrd1-mediated ERAD is critical for the proper maturation and function of developing B lymphocytes. In immature B cells, Sel1L–Hrd1-mediated ubiquitylation and turnover of the pre-BCR complex is critical for the developing B cell to transition from the large to small pre-B stage. In the absence of ERAD, the pre-BCR complex continually accumulates and migrates to the B cell surface, leading to excessive signaling and developmental blockade at the large pre-B stage (Ji et al., 2016; Yang et al., 2018). Moreover, in mature B cells, Hrd1 degrades the cell death receptor Fas (also known as cluster of differentiation 95, Cd95) to protect B cells from Fas-mediated apoptosis (Kong et al., 2016).

In summary, while ERAD function has previously mostly been associated with the triage of misfolded proteins in the ER, thus exerting a quality control function (e.g. of prohormones), several recent studies in physiological settings now demonstrate that ERAD also works as a quantity control mechanism to regulate the abundance of folding-competent substrates, such as Crebh, Ire1α and the pre-BCR. Unlike its role in quality control, which safeguards protein maturation processes in the ER, ERAD-mediated quantity control restricts or restrains the abundance and function of its substrates and so fine-tunes associated downstream processes to their optimal levels. It is important to note here that it is difficult to state definitively whether or not the substrate proteins of ERAD are misfolded or folding competent. Theoretically, even a small unfolded segment may suffice to form a degron in the protein, which can then be targeted to the ERAD pathway. However, an ERAD deficiency could affect the folding environment of the ER, and/or post-ER trafficking, which may depend on the intrinsic folding and biochemical properties of the substrate, as well as the levels of various chaperones in the ER.

ERAD in regulating gene transcription

A direct communication from the ER to gene transcription in the nucleus is a characteristic of UPR, such as the axes involving Ire1α and the spliced form of X-box binding protein 1 (Xbp1s), or protein kinase R (PKR)-like ER kinase (PERK), eukaryotic translation initiation factor 2A (eIF2α) and activating transcription factor 4 (Atf4) or Atf6 activation (Walter and Ron, 2011). But whether or not ERAD exerts a similar control over nuclear transcription remains underappreciated, especially in vivo. In yeast, early studies have shown that ubiquitin and/or proteasome-dependent processing regulates the abundance of the ER-associated transcription factor suppressor of Ty 23 (Spt23) and its paralog Mga2 to regulate fatty acid metabolism (Hoppe et al., 2000; Rape et al., 2001). Recent studies in mouse models highlight the importance of ER protein turnover in the regulation of gene transcription in various physiological settings (Fig. 1D).

In the liver, Sel1L–Hrd1 regulates the transcription of Fgf21 gene via degradation of the ER-resident transcription factor Crebh. As mentioned above, in the absence of Sel1L–Hrd1, Crebh accumulates and translocates to the nucleus following its proteolysis at Golgi to trigger the expression of many target genes, including Fgf21 (Bhattacharya et al., 2018; Wei et al., 2018a). As Sel1L–Hrd1 expression is controlled by nutrient fasting-feeding and growth, these studies suggest that hepatic ERAD activity directly links physiological cues to gene transcription and systemic energy metabolism in the body. In addition, as described above, Sel1L-Hrd1-mediated ERAD regulates the turnover of Ire1α, which is responsible for the production of the key UPR transcription factor Xbp1s (Sun et al., 2015). This ERAD–UPR interaction is required for the control of ER capacity and function, pointing to a feedback loop between ERAD and UPR within the cell.

In addition, Hrd1 may directly mediate the degradation of nuclear transcription factors. Examples include B lymphocyte-induced maturation protein-1 (Blimp1; also known as PRDM1), a transcriptional repressor of the MHC-II gene in dendritic cells that is crucial for the pathogenesis of myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE) (Yang et al., 2014), nuclear factor erythroid 2-related factor 2 (Nrf2, also known as NFE2L2), a regulator of anti-oxidant pathways in the liver, conferring protection from ROS-induced liver cirrhosis (Wu et al., 2014), p27kip1 (CDKN1B), a cyclin-dependent kinase inhibitor in T cells, which regulates their proliferation potential (Xu et al., 2016), and peroxisome proliferator-activated receptor γ coactivator 1β (Pgc1β), which regulates mitochondrial biogenesis in the adipose tissue, protecting from obesity development (Fujita et al., 2015). However, the underlying molecular mechanism with regard to how Hrd1 recognizes nuclear substrates and whether this depends on Sel1L remains unclear.

Collectively, these studies reveal exciting regulatory cascades from protein degradation at the ER membrane to gene transcription in the nucleus (Fig. 1D), which likely are the means for how ERAD controls the responses to in vivo physiological cues. They also position Sel1L–Hrd1 ERAD as a central node in linking physiological cues to gene transcription. More such examples of ERAD-mediated gene regulation in vivo will likely emerge from future investigations.

ERAD in disease

Disease-causing mutations often give rise to protein misfolding and thus, in theory, would create perfect ERAD substrates. However, the question then is how these pathogenic mutants cause disease if ERAD is functional. Two recent papers on prohormones have provided some insights into the pathological significance of ERAD in dealing with pathogenic mutations (Kim et al., 2018; Shi et al., 2017). The mutants obtained from diabetes insipidus patients (proAVP-G57S, Gly57 to Ser and ΔE47, deletion of Glu47) and obese patients (POMC-C28F, Cys28 to Phe) are prone to forming intracellular aggregates (Birk et al., 2009; Creemers et al., 2008; Ito et al., 1999; Rittig et al., 1996). ERAD may become insufficient in the face of an overwhelming amount of misfolded mutant proteins or, alternatively, certain disease-causing mutant proteins may evade ERAD (Kim et al., 2018; Shi et al., 2017). These pathogenic mutations then may form high-molecular-mass protein aggregates, which interfere with their wild-type counterparts in a dominant-negative manner. In the case of C28F POMC, the mutant forms higher molecular mass protein aggregates via the unpaired cysteine residue at position 50 (Kim et al., 2018). Indeed, the pathogenic effect of the C28F mutation can be suppressed by an intragenic mutation at C50 to a serine or alanine residue (Kim et al., 2018). These recent revelations, and the implication that ERAD may become insufficient in the face of disease mutations, also point to the potential therapeutic intervention of targeting ERAD-mediated turnover of disease mutants.

In this context, small molecules targeting Sel1L–Hrd1-mediated ERAD may have significant therapeutic value. LS-101 and LS-102 are two classes of Hrd1 inhibitors that have been demonstrated to suppress the progression of rheumatoid arthritis – a disease in which Hrd1 expression is found to be highly elevated (Yagishita et al., 2012). Additionally, selective inhibition of Hrd1 by LS-102 has been shown to increase Pgc1β levels in white adipose tissues, leading to reduced fat accumulation and increased mitochondrial numbers in mouse models (Fujita et al., 2015), further underscoring the therapeutic importance of this regulatory axis in obesity treatment. Furthermore, CB5083, an inhibitor of the ERAD-associated Vcp ATPase, has shown promise as a therapeutic agent in combating both solid and hematological tumor models (Anderson et al., 2015; Le Moigne et al., 2017). Finally, as Sel1L is indispensable for Hrd1 stability and ERAD function, small molecules that target the interaction between Sel1L and Hrd1 may also have significant therapeutic potential.

Conclusions and further questions

Sel1L–Hrd1-mediated ERAD has emerged as a crucial determinant of normal physiology and as a sentinel against disease pathogenesis in the body. Recent studies of ERAD-deficient animal models highlight three features of ERAD (Fig. 1B–D) that are crucial for maintaining physiological homeostasis. First, constitutive ERAD can function to maintain optimal levels of substrate proteins within the cell. Second, ERAD activity can perform both quality control of misfolded proteins (e.g. proAvp, Pomc and Lpl) and quantity control of maturation-competent proteins (e.g. Crebh, preBCR and Ire1α); this ensures the abundance of substrate proteins and maintains the desired levels of downstream processes. Third, ERAD is also capable of integrating extracellular cues to regulate nuclear gene transcription by controlling the turnover of ER-resident transcriptional modulators. Future explorations into both the physiological and pathological aspects of ERAD as part of a macroscale signaling network are thus indispensable.

Nevertheless, a number of key questions remain. For instance, we still lack the means to accurately measure and quantify ERAD capacity and function in a (patho)physiological context. To better elucidate ERAD biology, a reliable tool or readout is required that allows to directly assess ERAD activity, especially in a physiological setting, akin to the tools available for measuring UPR activity (e.g. Ire1α and Perk phosphorylation, Xbp1 splicing) (see Box 2), or autophagic flux (such as LC3 lipidation or p62 degradation).

Box 2. How to accurately quantify stress levels in the ER.

  • In order to accurately quantify stress levels in the ER, it is necessary to: (1) measure the level of phosphorylation of the UPR sensors Ire1α and Perk to accurately quantify the ‘level’ of ER stress (Yang et al., 2010); (2) measure activation of downstream effectors of Ire1α and Perk, namely, Xbp1 mRNA splicing assessment (via RT-PCR) and the ratio of phosphorylation of eIF2α to total eIF2α protein level (via western blotting) (Sha et al., 2009); and (3) measure the expression of downstream target genes, although this cannot be used alone, to assess ER stress level under pathophysiological conditions.

 We and others have verified the following antibodies as dependable tools for UPR assessment (DeNicola et al., 2015; He et al., 2012; Sun et al., 2019; Yang et al., 2013); other antibodies (e.g. against Atf6) require further quality assessment and improvement in specificity:

• Ire1α, Cell Signaling #3294 (use together with phos-tag western blotting)

  • Xbp1s, Cell Signaling #83418

  • Perk, Cell Signaling #3192

  • Phospho-eIF2α, Cell Signaling #3597

  • eIF2α-total, Cell Signaling #9722

  • Atf4, Cell Signaling #11815

Another important question is what defines ERAD substrate specificity. With the identification of many endogenous substrates (Table 2), we are now at a better position to address whether substrate recognition by ERAD is relatively stochastic, largely driven by local stoichiometric concentrations, or whether specific chaperones (e.g. Os9 or Grp78) intervene to make it a deterministic or ‘intelligent’ choice. Furthermore, while several recent studies using mouse models have demonstrated that changes in the physiological states of the body (e.g. nutrient fasting-feeding, water deprivation and growth) induce the expression of ERAD components in specific cell types (Bhattacharya et al., 2018; Kim et al., 2018; Shi et al., 2017; Wei et al., 2018a), an open area of research is to identify the underlying signaling pathways. Achieving this might also make it possible to develop therapeutic approaches aimed at fine-tuning ERAD function within the cell.

One key issue in ERAD research is the popular, but misguided, belief that ERAD deficiency is always associated with massive ER stress and cell death. However, that does not appear to hold true in certain cell types under physiological settings (Bhattacharya et al., 2018; Kim et al., 2018; Shi et al., 2017; Wei et al., 2018a). Instead, specific ERAD substrates, either via loss- or gain-of-function, appear to contribute collectively to the phenotypes of ERAD-deficient mice. While current popular belief is that disease-causing proteins are misfolded and exert their pathogenicity by triggering ER stress and activating UPR, another possibility, as discussed above, is that at least some of these disease mutants may bypass ERAD-mediated quality control. This often leads to the abrogation of function of the properly folded ‘bystander’ proteins along the way, while only triggering very mild, if any, UPR owing to mechanisms including, but not limited to, an adaptation in the ER and/or compensation from other cellular protein clearance systems. Further research emphasis on these aspects is needed to delineate the emerging interplay between these mutant proteins and ERAD function in the context of disease pathogenesis.

Another challenging area that warrants further investigation is the inevitable crosstalk among the three key quality control systems within the cell – ERAD, UPR and autophagy (or ER-phagy) – in terms of how and when these processes complement each other, or act in a redundant or, possibly, competitive manner, especially in the context of substrate choice, allocation of cellular resources and disease development. Animal models that bear tissue-specific deficiencies in ERAD, UPR and autophagy, either singly or in combination with each other, will be necessary to tease apart these challenging but critical questions. Probing into these outstanding questions will allow us to visualize, in the whole organism, the intricate network formed by these cellular quality control systems in enabling cellular function in diverse contexts of health and disease.

Acknowledgements

We apologize to colleagues whose works were not cited due to the space limitations.

Footnotes

Competing interests

The authors declare no competing or financial interests.

Funding

The work in the Qi laboratory is supported by the National Institutes of Health (NIH; R01GM113188, R35DM130292, R01DK105393, R01DK111174, R01DK120047, R01DK120330, R01DK117639), the University of Michigan Protein Folding Diseases Initiative, Juvenile Diabetes Research Foundation United States of America (JDRF) and American Diabetes Association (ADA). A.B. was a recipient of an American Heart Association Predoctoral Fellowship (16PRE29750001). L.Q. is the recipient of the Junior Faculty and Career Development Awards from the ADA. Deposited in PMC for release after 12 months.

References

  1. Altier C., Garcia-Caballero A., Simms B., You H., Chen L., Walcher J., Tedford H. W., Hermosilla T. and Zamponi G. W. (2011). The cavbeta subunit prevents RFP2-mediated ubiquitination and proteasomal degradation of L-type channels. Nat. Neurosci. 14, 173-180. 10.1038/nn.2712 [DOI] [PubMed] [Google Scholar]
  2. Anderson D. J., Le Moigne R., Djakovic S., Kumar B., Rice J., Wong S., Wang J., Yao B., Valle E., Kiss von Soly S. et al. (2015). Targeting the AAA ATPase p97 as an approach to treat cancer through disruption of protein homeostasis. Cancer Cell 28, 653-665. 10.1016/j.ccell.2015.10.002 [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Araki K. and Nagata K. (2011). Protein folding and quality control in the ER. Cold Spring Harb. Perspect. Biol. 3, a007526 10.1101/cshperspect.a007526 [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Aridor M. and Balch W. E. (1999). Integration of endoplasmic reticulum signaling in health and disease. Nat. Med. 5, 745-751. 10.1038/10466 [DOI] [PubMed] [Google Scholar]
  5. Baldridge R. D. and Rapoport T. A. (2016). Autoubiquitination of the Hrd1 ligase triggers protein retrotranslocation in ERAD. Cell 166, 394-407. 10.1016/j.cell.2016.05.048 [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Benhamron S., Hadar R., Iwawaky T., So J.-S., Lee A.-H. and Tirosh B. (2014). Regulated IRE1-dependent decay participates in curtailing immunoglobulin secretion from plasma cells. Eur. J. Immunol. 44, 867-876. 10.1002/eji.201343953 [DOI] [PubMed] [Google Scholar]
  7. Bernasconi R., Galli C., Calanca V., Nakajima T. and Molinari M. (2010). Stringent requirement for HRD1, SEL1L, and OS-9/XTP3-B for disposal of ERAD-LS substrates. J. Cell Biol. 188, 223-235. 10.1083/jcb.200910042 [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Bhattacharya A., Sun S., Wang H., Liu M., Long Q., Yin L., Kersten S., Zhang K. and Qi L. (2018). Hepatic Sel1L-Hrd1 ER-associated degradation (ERAD) manages FGF21 levels and systemic metabolism via CREBH. EMBO J. 37, e99277 10.15252/embj.201899277 [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Birk J., Friberg M. A., Prescianotto-Baschong C., Spiess M. and Rutishauser J. (2009). Dominant pro-vasopressin mutants that cause diabetes insipidus form disulfide-linked fibrillar aggregates in the endoplasmic reticulum. J. Cell Sci. 122, 3994-4002. 10.1242/jcs.051136 [DOI] [PubMed] [Google Scholar]
  10. BonDurant L. D., Ameka M., Naber M. C., Markan K. R., Idiga S. O., Acevedo M. R., Walsh S. A., Ornitz D. M. and Potthoff M. J. (2017). FGF21 regulates metabolism through adipose-dependent and -independent mechanisms. Cell Metab. 25, 935-944.e4. 10.1016/j.cmet.2017.03.005 [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Braakman I. and Bulleid N. J. (2011). Protein folding and modification in the mammalian endoplasmic reticulum. Annu. Rev. Biochem. 80, 71-99. 10.1146/annurev-biochem-062209-093836 [DOI] [PubMed] [Google Scholar]
  12. Carvalho P., Stanley A. M. and Rapoport T. A. (2010). Retrotranslocation of a misfolded luminal ER protein by the ubiquitin-ligase Hrd1p. Cell 143, 579-591. 10.1016/j.cell.2010.10.028 [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Christianson J. C. and Ye Y. (2014). Cleaning up in the endoplasmic reticulum: ubiquitin in charge. Nat. Struct. Mol. Biol. 21, 325-335. 10.1038/nsmb.2793 [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. **Christianson J. C., Shaler T. A., Tyler R. E. and Kopito R. R. (2008). OS-9 and GRP94 deliver mutant alpha1-antitrypsin to the Hrd1-SEL1L ubiquitin ligase complex for ERAD. Nat. Cell Biol. 10, 272-282. 10.1038/nsmb.2793 [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Christianson J. C., Olzmann J. A., Shaler T. A., Sowa M. E., Bennett E. J., Richter C. M., Tyler R. E., Greenblatt E. J., Harper J. W. and Kopito R. R. (2012). Defining human ERAD networks through an integrative mapping strategy. Nat. Cell Biol. 14, 93-105. 10.1038/ncb2383 [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Creemers J. W. M., Lee Y. S., Oliver R. L., Bahceci M., Tuzcu A., Gokalp D., Keogh J., Herber S., White A., O'Rahilly S. et al. (2008). Mutations in the amino-terminal region of proopiomelanocortin (POMC) in patients with early-onset obesity impair POMC sorting to the regulated secretory pathway. J. Clin. Endocrinol. Metab. 93, 4494-4499. 10.1210/jc.2008-0954 [DOI] [PubMed] [Google Scholar]
  17. Deng Y., Wang Z. V., Gordillo R., Zhu Y., Ali A., Zhang C., Wang X., Shao M., Zhang Z., Iyengar P. et al. (2018). Adipocyte Xbp1s overexpression drives uridine production and reduces obesity. Mol. Metab. 11, 1-17. 10.1016/j.molmet.2018.02.013 [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. DeNicola G. M., Chen P.-H., Mullarky E., Sudderth J. A., Hu Z., Wu D., Tang H., Xie Y., Asara J. M., Huffman K. E. et al. (2015). NRF2 regulates serine biosynthesis in non-small cell lung cancer. Nat. Genet. 47, 1475-1481. 10.1038/ng.3421 [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Dougan S. K., Hu C.-C. A., Paquet M.-E., Greenblatt M. B., Kim J., Lilley B. N., Watson N. and Ploegh H. L. (2011). Derlin-2-deficient mice reveal an essential role for protein dislocation in chondrocytes. Mol. Cell. Biol. 31, 1145-1159. 10.1128/MCB.00967-10 [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Ernst R., Mueller B., Ploegh H. L. and Schlieker C. (2009). The otubain YOD1 is a deubiquitinating enzyme that associates with p97 to facilitate protein dislocation from the ER. Mol. Cell 36, 28-38. 10.1016/j.molcel.2009.09.016 [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Eura Y., Yanamoto H., Arai Y., Okuda T., Miyata T. and Kokame K. (2012). Derlin-1 deficiency is embryonic lethal, Derlin-3 deficiency appears normal, and Herp deficiency is intolerant to glucose load and ischemia in mice. PLoS ONE 7, e34298 10.1371/journal.pone.0034298 [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Fang S., Ferrone M., Yang C., Jensen J. P., Tiwari S. and Weissman A. M. (2001). The tumor autocrine motility factor receptor, gp78, is a ubiquitin protein ligase implicated in degradation from the endoplasmic reticulum. Proc. Natl. Acad. Sci. USA 98, 14422-14427. 10.1073/pnas.251401598 [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Fisher F. M., Kleiner S., Douris N., Fox E. C., Mepani R. J., Verdeguer F., Wu J., Kharitonenkov A., Flier J. S., Maratos-Flier E. et al. (2012). FGF21 regulates PGC-1alpha and browning of white adipose tissues in adaptive thermogenesis. Genes Dev. 26, 271-281. 10.1101/gad.177857.111 [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Foresti O., Ruggiano A., Hannibal-Bach H. K., Ejsing C. S. and Carvalho P. (2013). Sterol homeostasis requires regulated degradation of squalene monooxygenase by the ubiquitin ligase Doa10/Teb4. eLife 2, e00953 10.7554/eLife.00953 [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Francisco A. B., Singh R., Li S., Vani A. K., Yang L., Munroe R. J., Diaferia G., Cardano M., Biunno I., Qi L. et al. (2010). Deficiency of suppressor enhancer lin12 1 like (SEL1L) in mice leads to systemic endoplasmic reticulum stress and embryonic lethality. J. Biol. Chem. 285, 13694-13703. 10.1074/jbc.M109.085340 [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Fujita H., Yagishita N., Aratani S., Saito-Fujita T., Morota S., Yamano Y., Hansson M. J., Inazu M., Kokuba H., Sudo K. et al. (2015). The E3 ligase synoviolin controls body weight and mitochondrial biogenesis through negative regulation of PGC-1beta. EMBO J. 34, 1042-1055. 10.15252/embj.201489897 [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Goldfinger M., Laviad E. L., Hadar R., Shmuel M., Dagan A., Park H., Merrill A. H. Jr., Ringel I., Futerman A. H. and Tirosh B. (2009). De novo ceramide synthesis is required for N-linked glycosylation in plasma cells. J. Immunol. 182, 7038-7047. 10.4049/jimmunol.0802990 [DOI] [PubMed] [Google Scholar]
  28. Guerriero C. J. and Brodsky J. L. (2012). The delicate balance between secreted protein folding and endoplasmic reticulum-associated degradation in human physiology. Physiol. Rev. 92, 537-576. 10.1152/physrev.00027.2011 [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Hampton R. Y. (2000). ER stress response: getting the UPR hand on misfolded proteins. Curr. Biol. 10, R518-R521. 10.1016/S0960-9822(00)00583-2 [DOI] [PubMed] [Google Scholar]
  30. Hassink G., Kikkert M., van Voorden S., Lee S.-J., Spaapen R., van Laar T., Coleman C. S., Bartee E., Früh K., Chau V. et al. (2005). TEB4 is a C4HC3 RING finger-containing ubiquitin ligase of the endoplasmic reticulum. Biochem. J. 388, 647-655. 10.1042/BJ20041241 [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. He Y., Beatty A., Han X., Ji Y., Ma X., Adelstein R. S., Yates J. R., Kemphues K. and Qi L. (2012). Non-muscle myosin IIB links cytoskeleton to IRE1α signaling during ER stress. Dev. Cell 23, 1141-1152. 10.1016/j.devcel.2012.11.006 [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Hegde R. S. and Lingappa V. R. (1997). Membrane protein biogenesis: regulated complexity at the endoplasmic reticulum. Cell 91, 575-582. 10.1016/S0092-8674(00)80445-6 [DOI] [PubMed] [Google Scholar]
  33. Hegde R. S. and Ploegh H. L. (2010). Quality and quantity control at the endoplasmic reticulum. Curr. Opin. Cell Biol. 22, 437-446. 10.1016/j.ceb.2010.05.005 [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Hess D. A., Humphrey S. E., Ishibashi J., Damsz B., Lee A. H., Glimcher L. H. and Konieczny S. F. (2011). Extensive pancreas regeneration following acinar-specific disruption of Xbp1 in mice. Gastroenterology 141, 1463-1472. 10.1053/j.gastro.2011.06.045 [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Hondares E., Rosell M., Gonzalez F. J., Giralt M., Iglesias R. and Villarroya F. (2010). Hepatic FGF21 expression is induced at birth via PPARalpha in response to milk intake and contributes to thermogenic activation of neonatal brown fat. Cell Metab. 11, 206-212. 10.1016/j.cmet.2010.02.001 [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Hoppe T., Matuschewski K., Rape M., Schlenker S., Ulrich H. D. and Jentsch S. (2000). Activation of a membrane-bound transcription factor by regulated ubiquitin/proteasome-dependent processing. Cell 102, 577-586. 10.1016/S0092-8674(00)00080-5 [DOI] [PubMed] [Google Scholar]
  37. Hu Y., Gao Y., Zhang M., Deng K.-Y., Singh R., Tian Q., Gong Y., Pan Z., Liu Q., Boisclair Y. R. et al. (2019). Endoplasmic Reticulum-Associated Degradation (ERAD) has a critical role in supporting glucose-stimulated insulin secretion in pancreatic beta-cells. Diabetes 68, 733-746. 10.2337/db18-0624 [DOI] [PubMed] [Google Scholar]
  38. Hwang J. and Qi L. (2018). Quality control in the endoplasmic reticulum: crosstalk between ERAD and UPR pathways. Trends Biochem. Sci. 43, 593-605. 10.1016/j.tibs.2018.06.005 [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Iida K., Li Y., McGrath B. C., Frank A. and Cavener D. R. (2007). PERK eIF2 alpha kinase is required to regulate the viability of the exocrine pancreas in mice. BMC Cell Biol. 8, 38 10.1186/1471-2121-8-38 [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Inagaki T., Dutchak P., Zhao G., Ding X., Gautron L., Parameswara V., Li Y., Goetz R., Mohammadi M., Esser V. et al. (2007). Endocrine regulation of the fasting response by PPARalpha-mediated induction of fibroblast growth factor 21. Cell Metab. 5, 415-425. 10.1016/j.cmet.2007.05.003 [DOI] [PubMed] [Google Scholar]
  41. Inagaki T., Lin V. Y., Goetz R., Mohammadi M., Mangelsdorf D. J. and Kliewer S. A. (2008). Inhibition of growth hormone signaling by the fasting-induced hormone FGF21. Cell Metab. 8, 77-83. 10.1016/j.cmet.2008.05.006 [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Ito M., Jameson J. L. and Ito M. (1997). Molecular basis of autosomal dominant neurohypophyseal diabetes insipidus. Cellular toxicity caused by the accumulation of mutant vasopressin precursors within the endoplasmic reticulum. J. Clin. Invest. 99, 1897-1905. 10.1172/JCI119357 [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Ito M., Yu R. N., Jameson J. L. and Ito M. (1999). Mutant vasopressin precursors that cause autosomal dominant neurohypophyseal diabetes insipidus retain dimerization and impair the secretion of wild-type proteins. J. Biol. Chem. 274, 9029-9037. 10.1074/jbc.274.13.9029 [DOI] [PubMed] [Google Scholar]
  44. Ji Y., Kim H., Yang L., Sha H., Roman C. A., Long Q. and Qi L. (2016). The Sel1L-Hrd1 endoplasmic reticulum-associated degradation complex manages a key checkpoint in b cell development. Cell Rep. 16, 2630-2640. 10.1016/j.celrep.2016.08.003 [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Jiang S., Yan C., Fang Q.-C., Shao M.-L., Zhang Y.-L., Liu Y., Deng Y.-P., Shan B., Liu J.-Q., Li H.-T. et al. (2014). Fibroblast growth factor 21 is regulated by the IRE1alpha-XBP1 branch of the unfolded protein response and counteracts endoplasmic reticulum stress-induced hepatic steatosis. J. Biol. Chem. 289, 29751-29765. 10.1074/jbc.M114.565960 [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Johnson B. M. and DeBose-Boyd R. A. (2018). Underlying mechanisms for sterol-induced ubiquitination and ER-associated degradation of HMG CoA reductase. Semin. Cell Dev. Biol. 81, 121-128. 10.1016/j.semcdb.2017.10.019 [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Kaser A., Lee A.-H., Franke A., Glickman J. N., Zeissig S., Tilg H., Nieuwenhuis E. E. S., Higgins D. E., Schreiber S., Glimcher L. H. et al. (2008). XBP1 links ER stress to intestinal inflammation and confers genetic risk for human inflammatory bowel disease. Cell 134, 743-756. 10.1016/j.cell.2008.07.021 [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Kharitonenkov A., Shiyanova T. L., Koester A., Ford A. M., Micanovic R., Galbreath E. J., Sandusky G. E., Hammond L. J., Moyers J. S., Owens R. A. et al. (2005). FGF-21 as a novel metabolic regulator. J. Clin. Invest. 115, 1627-1635. 10.1172/JCI23606 [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. Kikkert M., Doolman R., Dai M., Avner R., Hassink G., van Voorden S., Thanedar S., Roitelman J., Chau V. and Wiertz E. (2004). Human HRD1 is an E3 ubiquitin ligase involved in degradation of proteins from the endoplasmic reticulum. J. Biol. Chem. 279, 3525-3534. 10.1074/jbc.M307453200 [DOI] [PubMed] [Google Scholar]
  50. Kim G. H., Shi G., Somlo D. R. M., Haataja L., Song S., Long Q., Nillni E. A., Low M. J., Arvan P., Myers M. G. et al. (2018). Hypothalamic ER-associated degradation regulates POMC maturation, feeding and age-associated obesity. J. Clin. Invest. 128, 1125-1140. 10.1172/JCI96420 [DOI] [PMC free article] [PubMed] [Google Scholar]
  51. Kong S., Yang Y., Xu Y., Wang Y., Zhang Y., Melo-Cardenas J., Xu X., Gao B., Thorp E. B., Zhang D. D. et al. (2016). Endoplasmic reticulum-resident E3 ubiquitin ligase Hrd1 controls B-cell immunity through degradation of the death receptor CD95/Fas. Proc. Natl. Acad. Sci. USA 113, 10394-10399. 10.1073/pnas.1606742113 [DOI] [PMC free article] [PubMed] [Google Scholar]
  52. Le Moigne R., Aftab B. T., Djakovic S., Dhimolea E., Valle E., Murnane M., King E. M., Soriano F., Menon M. K., Wu Z. Y. et al. (2017). The p97 Inhibitor CB-5083 is a unique disrupter of protein homeostasis in models of multiple myeloma. Mol. Cancer Ther. 16, 2375-2386. 10.1158/1535-7163.MCT-17-0233 [DOI] [PubMed] [Google Scholar]
  53. Lee A.-H., Heidtman K., Hotamisligil G. S. and Glimcher L. H. (2011). Dual and opposing roles of the unfolded protein response regulated by IRE1alpha and XBP1 in proinsulin processing and insulin secretion. Proc. Natl. Acad. Sci. USA 108, 8885-8890. 10.1073/pnas.1105564108 [DOI] [PMC free article] [PubMed] [Google Scholar]
  54. Lilley B. N. and Ploegh H. L. (2004). A membrane protein required for dislocation of misfolded proteins from the ER. Nature 429, 834-840. 10.1038/nature02592 [DOI] [PubMed] [Google Scholar]
  55. Liu Y., Choudhury P., Cabral C. M. and Sifers R. N. (1997). Intracellular disposal of incompletely folded human alpha1-antitrypsin involves release from calnexin and post-translational trimming of asparagine-linked oligosaccharides. J. Biol. Chem. 272, 7946-7951. 10.1074/jbc.272.12.7946 [DOI] [PubMed] [Google Scholar]
  56. Liu T.-F., Tang J.-J., Li P.-S., Shen Y., Li J.-G., Miao H.-H., Li B.-L. and Song B.-L. (2012). Ablation of gp78 in liver improves hyperlipidemia and insulin resistance by inhibiting SREBP to decrease lipid biosynthesis. Cell Metab. 16, 213-225. 10.1016/j.cmet.2012.06.014 [DOI] [PubMed] [Google Scholar]
  57. Luo H., Jiang M., Lian G., Liu Q., Shi M., Li T. Y., Song L., Ye J., He Y., Yao L. et al. (2018). AIDA selectively mediates downregulation of fat synthesis enzymes by ERAD to retard intestinal fat absorption and prevent obesity. Cell Metab. 27, 843-853.e6. 10.1016/j.cmet.2018.02.021 [DOI] [PubMed] [Google Scholar]
  58. Medel B., Costoya C., Fernandez D., Pereda C., Lladser A., Sauma D., Pacheco R., Iwawaki T., Salazar-Onfray F. and Osorio F. (2018). IRE1alpha activation in bone marrow-derived dendritic cells modulates innate recognition of melanoma cells and favors CD8+ T cell priming. Front. Immunol. 9, 3050 10.3389/fimmu.2018.03050 [DOI] [PMC free article] [PubMed] [Google Scholar]
  59. Merulla J., Fasana E., Soldà T. and Molinari M. (2013). Specificity and regulation of the endoplasmic reticulum-associated degradation machinery. Traffic 14, 767-777. 10.1111/tra.12068 [DOI] [PubMed] [Google Scholar]
  60. Meyer H., Bug M. and Bremer S. (2012). Emerging functions of the VCP/p97 AAA-ATPase in the ubiquitin system. Nat. Cell Biol. 14, 117-123. 10.1038/ncb2407 [DOI] [PubMed] [Google Scholar]
  61. Mueller B., Lilley B. N. and Ploegh H. L. (2006). SEL1L, the homologue of yeast Hrd3p, is involved in protein dislocation from the mammalian ER. J. Cell Biol. 175, 261-270. 10.1083/jcb.200605196 [DOI] [PMC free article] [PubMed] [Google Scholar]
  62. Mueller B., Klemm E. J., Spooner E., Claessen J. H. and Ploegh H. L. (2008). SEL1L nucleates a protein complex required for dislocation of misfolded glycoproteins. Proc. Natl. Acad. Sci. USA 105, 12325-12330. 10.1073/pnas.0805371105 [DOI] [PMC free article] [PubMed] [Google Scholar]
  63. Müller J. M. M., Deinhardt K., Rosewell I., Warren G. and Shima D. T. (2007). Targeted deletion of p97 (VCP/CDC48) in mouse results in early embryonic lethality. Biochem. Biophys. Res. Commun. 354, 459-465. 10.1016/j.bbrc.2006.12.206 [DOI] [PubMed] [Google Scholar]
  64. Niederreiter L., Fritz T. M. J., Adolph T. E., Krismer A.-M., Offner F. A., Tschurtschenthaler M., Flak M. B., Hosomi S., Tomczak M. F., Kaneider N. C. et al. (2013). ER stress transcription factor Xbp1 suppresses intestinal tumorigenesis and directs intestinal stem cells. J. Exp. Med. 210, 2041-2056. 10.1084/jem.20122341 [DOI] [PMC free article] [PubMed] [Google Scholar]
  65. Olzmann J. A., Kopito R. R. and Christianson J. C. (2013). The mammalian endoplasmic reticulum-associated degradation system. Cold Spring Harb. Perspect. Biol. 5, a013185 10.1101/cshperspect.a013185 [DOI] [PMC free article] [PubMed] [Google Scholar]
  66. Owen B. M., Bookout A. L., Ding X., Lin V. Y., Atkin S. D., Gautron L., Kliewer S. A. and Mangelsdorf D. J. (2013). FGF21 contributes to neuroendocrine control of female reproduction. Nat. Med. 19, 1153-1156. 10.1038/nm.3250 [DOI] [PMC free article] [PubMed] [Google Scholar]
  67. Owen B. M., Ding X., Morgan D. A., Coate K. C., Bookout A. L., Rahmouni K., Kliewer S. A. and Mangelsdorf D. J. (2014). FGF21 acts centrally to induce sympathetic nerve activity, energy expenditure, and weight loss. Cell Metab. 20, 670-677. 10.1016/j.cmet.2014.07.012 [DOI] [PMC free article] [PubMed] [Google Scholar]
  68. Phillips J. A., 3rd. (2003). Dominant-negative diabetes insipidus and other endocrinopathies. J. Clin. Invest. 112, 1641-1643. 10.1172/JCI20441 [DOI] [PMC free article] [PubMed] [Google Scholar]
  69. Qi L., Tsai B. and Arvan P. (2017). New insights into the physiological role of endoplasmic reticulum-associated degradation. Trends Cell Biol. 27, 430-440. 10.1016/j.tcb.2016.12.002 [DOI] [PMC free article] [PubMed] [Google Scholar]
  70. Rape M., Hoppe T., Gorr I., Kalocay M., Richly H. and Jentsch S. (2001). Mobilization of processed, membrane-tethered SPT23 transcription factor by CDC48(UFD1/NPL4), a ubiquitin-selective chaperone. Cell 107, 667-677. 10.1016/S0092-8674(01)00595-5 [DOI] [PubMed] [Google Scholar]
  71. Rittig S., Robertson G. L., Siggaard C., Kovacs L., Gregersen N., Nyborg J. and Pedersen E. B. (1996). Identification of 13 new mutations in the vasopressin-neurophysin II gene in 17 kindreds with familial autosomal dominant neurohypophyseal diabetes insipidus. Am. J. Hum. Genet. 58, 107-117. [PMC free article] [PubMed] [Google Scholar]
  72. Ron D. and Walter P. (2007). Signal integration in the endoplasmic reticulum unfolded protein response. Nat. Rev. Mol. Cell Biol. 8, 519-529. 10.1038/nrm2199 [DOI] [PubMed] [Google Scholar]
  73. Sha H., He Y., Chen H., Wang C., Zenno A., Shi H., Yang X., Zhang X. and Qi L. (2009). The IRE1alpha-XBP1 pathway of the unfolded protein response is required for adipogenesis. Cell Metab. 9, 556-564. 10.1016/j.cmet.2009.04.009 [DOI] [PMC free article] [PubMed] [Google Scholar]
  74. Sha H., Sun S., Francisco A. B., Ehrhardt N., Xue Z., Liu L., Lawrence P., Mattijssen F., Guber R. D., Panhwar M. S. et al. (2014a). The ER-associated degradation adaptor protein Sel1L regulates LPL secretion and lipid metabolism. Cell Metab. 20, 458-470. 10.1016/j.cmet.2014.06.015 [DOI] [PMC free article] [PubMed] [Google Scholar]
  75. Sha H., Yang L., Liu M., Xia S., Liu Y., Liu F., Kersten S. and Qi L. (2014b). Adipocyte spliced form of x-box-binding protein 1 promotes adiponectin multimerization and systemic glucose homeostasis. Diabetes 63, 867-879. 10.2337/db13-1067 [DOI] [PMC free article] [PubMed] [Google Scholar]
  76. Shao M., Shan B., Liu Y., Deng Y., Yan C., Wu Y., Mao T., Qiu Y., Zhou Y., Jiang S. et al. (2014). Hepatic IRE1alpha regulates fasting-induced metabolic adaptive programs through the XBP1s-PPARalpha axis signalling. Nat. Commun. 5, 3528 10.1038/ncomms4528 [DOI] [PubMed] [Google Scholar]
  77. Shi G., Somlo D., Kim G. H., Prescianotto-Baschong C., Sun S., Beuret N., Long Q., Rutishauser J., Arvan P., Spiess M. et al. (2017). ER-associated degradation is required for vasopressin prohormone processing and systemic water homeostasis. J. Clin. Invest. 127, 3897-3912. 10.1172/JCI94771 [DOI] [PMC free article] [PubMed] [Google Scholar]
  78. Sifers R. N., Brashears-Macatee S., Kidd V. J., Muensch H. and Woo S. L. (1988). A frameshift mutation results in a truncated alpha 1-antitrypsin that is retained within the rough endoplasmic reticulum. J. Biol. Chem. 263, 7330-7335. [PubMed] [Google Scholar]
  79. Smith M. H., Ploegh H. L. and Weissman J. S. (2011). Road to ruin: targeting proteins for degradation in the endoplasmic reticulum. Science 334, 1086-1090. 10.1126/science.1209235 [DOI] [PMC free article] [PubMed] [Google Scholar]
  80. Sun S., Shi G., Han X., Francisco A. B., Ji Y., Mendonça N., Liu X., Locasale J. W., Simpson K. W., Duhamel G. E. et al. (2014). Sel1L is indispensable for mammalian endoplasmic reticulum-associated degradation, endoplasmic reticulum homeostasis, and survival. Proc. Natl. Acad. Sci. USA 111, E582-E591. 10.1073/pnas.1318114111 [DOI] [PMC free article] [PubMed] [Google Scholar]
  81. Sun S., Shi G., Sha H., Ji Y., Han X., Shu X., Ma H., Inoue T., Gao B., Kim H. et al. (2015). IRE1a is an endogenous substrate of endoplasmic-reticulum-associated degradation. Nat. Cell Biol. 17, 1546-1555. 10.1038/ncb3266 [DOI] [PMC free article] [PubMed] [Google Scholar]
  82. Sun S., Louri R., Cohen S. B., Ji Y., Goodrich J. K., Poole A. C., Ley R. E., Denkers E. Y., Mcguckin M. A., Long Q. et al. (2016). Epithelial Sel1L is required for the maintenance of intestinal homeostasis. Mol. Biol. Cell 27, 483-490. 10.1091/mbc.e15-10-0724 [DOI] [PMC free article] [PubMed] [Google Scholar]
  83. Sun S., Kelekar S., Kliewer S. A. and Mangelsdorf D. J. (2019). The orphan nuclear receptor SHP regulates ER stress response by inhibiting XBP1s degradation. Genes Dev. 33, 1083-1094. 10.1101/gad.326868.119 [DOI] [PMC free article] [PubMed] [Google Scholar]
  84. Tsai Y. C., Leichner G. S., Pearce M. M. P., Wilson G. L., Wojcikiewicz R. J. H., Roitelman J. and Weissman A. M. (2012). Differential regulation of HMG-CoA reductase and Insig-1 by enzymes of the ubiquitin-proteasome system. Mol. Biol. Cell 23, 4484-4494. 10.1091/mbc.e12-08-0631 [DOI] [PMC free article] [PubMed] [Google Scholar]
  85. Tsuchiya Y., Saito M., Kadokura H., Miyazaki J.-I., Tashiro F., Imagawa Y., Iwawaki T. and Kohno K. (2018). IRE1-XBP1 pathway regulates oxidative proinsulin folding in pancreatic beta cells. J. Cell Biol. 217, 1287-1301. 10.1083/jcb.201707143 [DOI] [PMC free article] [PubMed] [Google Scholar]
  86. Tyler R. E., Pearce M. M. P., Shaler T. A., Olzmann J. A., Greenblatt E. J. and Kopito R. R. (2012). Unassembled CD147 is an endogenous endoplasmic reticulum-associated degradation substrate. Mol. Biol. Cell 23, 4668-4678. 10.1091/mbc.e12-06-0428 [DOI] [PMC free article] [PubMed] [Google Scholar]
  87. van der Goot A. T., Pearce M. M. P., Leto D. E., Shaler T. A. and Kopito R. R. (2018). Redundant and antagonistic roles of XTP3B and OS9 in decoding glycan and non-glycan degrons in ER-associated degradation. Mol. Cell 70, 516-530.e6. [DOI] [PMC free article] [PubMed] [Google Scholar]
  88. Vashistha N., Neal S. E., Singh A., Carroll S. M. and Hampton R. Y. (2016). Direct and essential function for Hrd3 in ER-associated degradation. Proc. Natl. Acad. Sci. USA 113, 5934-5939. 10.1073/pnas.1603079113 [DOI] [PMC free article] [PubMed] [Google Scholar]
  89. Vincenz-Donnelly L., Holthusen H., Körner R., Hansen E. C., Presto J., Johansson J., Sawarkar R., Hartl F. U. and Hipp M. S. (2018). High capacity of the endoplasmic reticulum to prevent secretion and aggregation of amyloidogenic proteins. EMBO J. 37, 337-350. 10.15252/embj.201695841 [DOI] [PMC free article] [PubMed] [Google Scholar]
  90. Volpi V. G., Ferri C., Fregno I., Del Carro U., Bianchi F., Scapin C., Pettinato E., Solda T., Feltri M. L., Molinari M. et al. (2019). Schwann cells ER-associated degradation contributes to myelin maintenance in adult nerves and limits demyelination in CMT1B mice. PLoS Genet. 15, e1008069 10.1371/journal.pgen.1008069 [DOI] [PMC free article] [PubMed] [Google Scholar]
  91. Walter P. and Ron D. (2011). The unfolded protein response: from stress pathway to homeostatic regulation. Science 334, 1081-1086. 10.1126/science.1209038 [DOI] [PubMed] [Google Scholar]
  92. Wang J. M., Qiu Y., Yang Z., Kim H., Qian Q., Sun Q., Zhang C., Yin L., Fang D., Back S. H. et al. (2018). IRE1alpha prevents hepatic steatosis by processing and promoting the degradation of select microRNAs. Sci. Signal. 11, eaa04617. 10.1126/scisignal.aao4617 [DOI] [PMC free article] [PubMed] [Google Scholar]
  93. Ward C. L., Omura S. and Kopito R. R. (1995). Degradation of CFTR by the ubiquitin-proteasome pathway. Cell 83, 121-127. 10.1016/0092-8674(95)90240-6 [DOI] [PubMed] [Google Scholar]
  94. Wei J., Chen L., Li F., Yuan Y., Wang Y., Xia W., Zhang Y., Xu Y., Yang Z., Gao B. et al. (2018a). HRD1-ERAD controls production of the hepatokine FGF21 through CREBH polyubiquitination. EMBO J. 37, e98942 10.15252/embj.201898942 [DOI] [PMC free article] [PubMed] [Google Scholar]
  95. Wei J., Yuan Y., Chen L., Xu Y., Zhang Y., Wang Y., Yang Y., Peek C. B., Diebold L., Yang Y. et al. (2018b). ER-associated ubiquitin ligase HRD1 programs liver metabolism by targeting multiple metabolic enzymes. Nat. Commun. 9, 3659 10.1038/s41467-018-06091-7 [DOI] [PMC free article] [PubMed] [Google Scholar]
  96. Wiseman R. L., Powers E. T., Buxbaum J. N., Kelly J. W. and Balch W. E. (2007). An adaptable standard for protein export from the endoplasmic reticulum. Cell 131, 809-821. 10.1016/j.cell.2007.10.025 [DOI] [PubMed] [Google Scholar]
  97. Wu T., Zhao F., Gao B., Tan C., Yagishita N., Nakajima T., Wong P. K., Chapman E., Fang D. and Zhang D. D. (2014). Hrd1 suppresses Nrf2-mediated cellular protection during liver cirrhosis. Genes Dev. 28, 708-722. 10.1101/gad.238246.114 [DOI] [PMC free article] [PubMed] [Google Scholar]
  98. Xiao Y., Xia T., Yu J., Deng Y., Liu H., Liu B., Chen S., Liu Y. and Guo F. (2016). Knockout of inositol-requiring enzyme 1alpha in pro-opiomelanocortin neurons decreases fat mass via increasing energy expenditure. Open Biol. 6, 160131 10.1098/rsob.160131 [DOI] [PMC free article] [PubMed] [Google Scholar]
  99. Xu T., Yang L., Yan C., Wang X., Huang P., Zhao F., Zhao L., Zhang M., Jia W., Wang X. et al. (2014). The IRE1alpha-XBP1 pathway regulates metabolic stress-induced compensatory proliferation of pancreatic beta-cells. Cell Res. 24, 1137-1140. 10.1038/cr.2014.55 [DOI] [PMC free article] [PubMed] [Google Scholar]
  100. Xu Y., Zhao F., Qiu Q., Chen K., Wei J., Kong Q., Gao B., Melo-Cardenas J., Zhang B., Zhang J. et al. (2016). The ER membrane-anchored ubiquitin ligase Hrd1 is a positive regulator of T-cell immunity. Nat. Commun. 7, 12073 10.1038/ncomms12073 [DOI] [PMC free article] [PubMed] [Google Scholar]
  101. Yagishita N., Aratani S., Leach C., Amano T., Yamano Y., Nakatani K., Nishioka K. and Nakajima T. (2012). RING-finger type E3 ubiquitin ligase inhibitors as novel candidates for the treatment of rheumatoid arthritis. Int. J. Mol. Med. 30, 1281-1286. 10.3892/ijmm.2012.1129 [DOI] [PMC free article] [PubMed] [Google Scholar]
  102. Yang L., Xue Z., He Y., Sun S., Chen H. and Qi L. (2010). A Phos-tag-based approach reveals the extent of physiological endoplasmic reticulum stress. PLoS ONE 5, e11621 10.1371/journal.pone.0011621 [DOI] [PMC free article] [PubMed] [Google Scholar]
  103. Yang L., Sha H., Davisson R. L. and Qi L. (2013). Phenformin activates the unfolded protein response in an AMP-activated protein kinase (AMPK)-dependent manner. J. Biol. Chem. 288, 13631-13638. 10.1074/jbc.M113.462762 [DOI] [PMC free article] [PubMed] [Google Scholar]
  104. Yang H., Qiu Q., Gao B., Kong S., Lin Z. and Fang D. (2014). Hrd1-mediated BLIMP-1 ubiquitination promotes dendritic cell MHCII expression for CD4 T cell priming during inflammation. J. Exp. Med. 211, 2467-2479. 10.1084/jem.20140283 [DOI] [PMC free article] [PubMed] [Google Scholar]
  105. Yang Y., Kong S., Zhang Y., Melo-Cardenas J., Gao B., Zhang Y., Zhang D. D., Zhang B., Song J., Thorp E. et al. (2018). The endoplasmic reticulum-resident E3 ubiquitin ligase Hrd1 controls a critical checkpoint in B cell development in mice. J. Biol. Chem. 293, 12934-12944. 10.1074/jbc.RA117.001267 [DOI] [PMC free article] [PubMed] [Google Scholar]
  106. Yao T., Deng Z., Gao Y., Sun J., Kong X., Huang Y., He Z., Xu Y., Chang Y., Yu K.-J. et al. (2017). Ire1alpha in pomc neurons is required for thermogenesis and glycemia. Diabetes 66, 663-673. 10.2337/db16-0533 [DOI] [PMC free article] [PubMed] [Google Scholar]
  107. Ye Y., Shibata Y., Yun C., Ron D. and Rapoport T. A. (2004). A membrane protein complex mediates retro-translocation from the ER lumen into the cytosol. Nature 429, 841-847. 10.1038/nature02656 [DOI] [PubMed] [Google Scholar]
  108. Younger J. M., Chen L., Ren H.-Y., Rosser M. F. N., Turnbull E. L., Fan C.-Y., Patterson C. and Cyr D. M. (2006). Sequential quality-control checkpoints triage misfolded cystic fibrosis transmembrane conductance regulator. Cell 126, 571-582. 10.1016/j.cell.2006.06.041 [DOI] [PubMed] [Google Scholar]
  109. Zhang P., McGrath B., Li S., Frank A., Zambito F., Reinert J., Gannon M., Ma K., McNaughton K. and Cavener D. R. (2002). The PERK eukaryotic initiation factor 2 alpha kinase is required for the development of the skeletal system, postnatal growth, and the function and viability of the pancreas. Mol. Cell. Biol. 22, 3864-3874. 10.1128/MCB.22.11.3864-3874.2002 [DOI] [PMC free article] [PubMed] [Google Scholar]
  110. Zhang W., Feng D., Li Y., Iida K., McGrath B. and Cavener D. R. (2006). PERK EIF2AK3 control of pancreatic beta cell differentiation and proliferation is required for postnatal glucose homeostasis. Cell Metab. 4, 491-497. 10.1016/j.cmet.2006.11.002 [DOI] [PubMed] [Google Scholar]
  111. Zhang K., Wang S., Malhotra J., Hassler J. R., Back S. H., Wang G., Chang L., Xu W., Miao H., Leonardi R. et al. (2011). The unfolded protein response transducer IRE1alpha prevents ER stress-induced hepatic steatosis. EMBO J. 30, 1357-1375. 10.1038/emboj.2011.52 [DOI] [PMC free article] [PubMed] [Google Scholar]
  112. Zhang T., Xu Y., Liu Y. and Ye Y. (2015). gp78 functions downstream of Hrd1 to promote degradation of misfolded proteins of the endoplasmic reticulum. Mol. Biol. Cell 26, 4438-4450. 10.1091/mbc.E15-06-0354 [DOI] [PMC free article] [PubMed] [Google Scholar]

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