Table 2.

Native folded substrates of ERAD, their subcellular localization and pathology.

Substrates	Subcellular localization	Cell type	Mouse model, phenotype and reference
Crebh	ER membrane, Nucleus	Hepatocytes	Alb-cre; Sel1L f/f, growth retardation, female fertility, Elevated Fgf21 levels (47) Alb-cre; Hrd1 f/f, growth retardation, female infertility, diurnal circadian behavior disruption, elevated circulating Fgf21 (48) Alb-cre; Hrd1 f/f, increased FA oxidation, TG lipolysis, lipophagy, and gluconeogenesis, impaired circadian profiles of circulating TG, FA and glucose (49)
Entpd5 Cpt2 Rmnd1 Hsd17b4	ER lumen Mitochondira Mitochondria Peroxisome	Hepatocytes	Alb-cre/Mx1-cre; Hrd1 f/f, reduction of body weight, triglyceride, protect mice from HFD-induced obesity (50)
Acly	Cytosol	Hepatocytes	db/db mice injected with Hrd1 adenovirus, represses lipid synthesis, ameliorates systemic glycemic control and insulin sensitivity, attenuates steatosis (51)
Hnf1a Hnf4a	Nucleus Nucleus	Hepatocytes	Sel1L +/-, increased serum total bile acid concentrations (52)
Nrf2	Nucleus	Hepatocytes	Hrd1 f/f mice are injected with Cre viruses, Suppression of anti-oxidation pathway, liver cirrhosis (53)
Wnt5a	ER lumen, secreted	Hepatocytes	Alb-cre; Sel1L f/f, Alb-cre; Hrd1 f/f, are prone to developing chemically induced liver tumors, exhibit excessive proliferation following injury (54)
Pgc1β	Nucleus	adipocytes	CAG-Cre-ER; Hrd1 f/f, CAG-Cre-ER; Hrd1 f/f; ob/ob or db/db, Adiponectin-cre; Hrd1 f/f, weight loss and lower accumulation of white adipose tissue (55)
SigmaR1	ER, cell membrane	adipocytes	Adiponectin or UCP1-cre; Sel1L f/f, Adiponectin or UCP1-cre; Hrd1 f/f, cold sensitive and exhibit mitochondrial dysfunction, affect ER-mitochondria contacts and mitochondrial dynamics (56)
Proinsulin	ER lumen, secreted	Pancreatic β-cells	RIP-cre; Sel1L f/f, Ins1-cre; Sel1L f/f, reduced glucose-stimulated insulin secretion, hyperglycemia, glucose intolerance (57)
Tgfbr1	Cell membrane	Pancreatic β-cells	Ins1-cre; Sel1L f/f, progressive hyperglycemia and glucose intolerance (58)
MafA	Nucleus	Pancreatic β-cells	db/db mice injected with AAV8-MIP-HRD1-GFP virus (59)
Ire1α	ER membrane	Enterocytes	Villin-cre; Sel1L f/f, susceptible to experimental colitis and inflammation-associated dysbiosis (60)
Gpat3 Dgat2 Mogat2	ER membrane	Enterocytes	Villin-cre; Aida f/f, HFD-induced obesity, increased fatty acid re-esterification and lipid absorption in intestine, postprandial hypertriglyceridemia (61)
Pomc	ER lumen, secreted	POMC neurons	POMC-cre; Sel1L f/f, age-associated obesity and hyperleptinemia, hyperphagia, impaired leptin sensitivity (62)
Pro-Avp	ER lumen, secreted	AVP-producing neurons	AVP-promoter driving cre; Sel1L f/f, central diabetes insipidus, intracellular ER retention of proAVP (63)