Autophagy in leukocytes and other cells: mechanisms, subsystem organization, selectivity, and links to innate immunity

Review of autophagy’s role in cytoplasmic homeostasis, innate and adaptive immune processes, inflammation, and the latest advances toward understanding these processes.

Abstract

Autophagy is a fundamental biologic process that fulfills general and specialized roles in cytoplasmic homeostasis. The cell-autonomous antimicrobial functions of autophagy have been established in the macrophage. These cells and other leukocytes continue to be the cells of choice in studying autophagy in immunity and inflammation. This review uses several model examples that will be of interest to leukocyte and cell biologists alike. Furthermore, it comprehensively covers the subsystems in autophagy as they apply to all mammalian cells and incorporates the recent progress in our understanding of how these modules come together—a topic that should be of interest to all readers.

Introduction

Autophagy is a ubiquitous eukaryotic intracellular homeostatic process affecting all cell types in multicellular organisms [1], including mammals, where it was first observed morphologically [2–4]. This review will cover the mechanisms of autophagy as a pathway in mammalian cells, with the emphasis on aspects underlying the role of autophagy in innate immunity [5]. To make it immediately relevant for researchers working in the field of leukocyte biology, we introduce below the topic using an example of the role of autophagy, with both its promise and current controversies, in control of Mycobacterium tuberculosis, a microbe parasitizing the macrophage. Of note, the examination of how autophagy intersects with bacteria is of relevance for fundamental principles of autophagy. This is best appreciated from parallels that exist [6, 7] between autophagy of mitochondria, which are organelles of endosymbiotic bacterial origin and are one of the earliest recognized targets of autophagy [2], and autophagy of intracellular bacteria [8].

MACROPHAGES AND AUTOPHAGIC CONTROL OF M. tuberculosis

Our present intense interest in autophagy has its roots in the antecedent studies with leukocytes conducted in late 1990s [9] on the mechanism of M. tuberculosis phagosome maturation block in infected macrophages [10–12]. That prior work led to one major conclusion—that there was something amiss with the production and dynamics of PI3P on mycobacterial phagosomes, which in turn, arrested membrane trafficking and precluded maturation and progression to phagolysosomes, where M. tuberculosis could presumably be eliminated [9, 12]. At that time, we wondered whether there was any naturally occurring cellular process that could be co-opted to help with PI3P production on intracellular membranes. One of the prominent candidates considered was the process of autophagy, which is exquisitely dependent on PI3P generation, necessary for the massive membrane remodeling involved in autophagosome formation and their maturation into autolysosomes [13, 14]. Thus, we used physiologic, immunologic, and pharmacological inducers of autophagy, such as starvation, IFN-γ, and rapamycin, and found that these maneuvers enabled maturation of M. tuberculosis phagosomes into compartments with lysosomal properties [15]. Moreover, induction of autophagy endowed maturing phagosomes with robust mycobactericidal properties [15], with several candidate effector molecules and processes underlying this phenomenon [16–18]. These ex vivo studies with cultured macrophages have led to validations in murine models of tuberculosis with a role in both controlling bacteria but also, perhaps more importantly, in suppressing damaging inflammation dominated by prolonged IL-1 signaling, extended Th17 response, and excessive neutrophilic infiltration [19–23].

The above chronological recap of autophagy studies in the context of tuberculosis shows just one line of investigation concerning the role of autophagy in antimicrobial defense. In the context of numerous other infectious agents, including other bacteria such as Salmonella [7, 24, 25], streptococci [26], and viruses [27], autophagy has been shown to play a significant role and has been reviewed extensively [7, 26, 28]. It is also important to point out that many microbes have well-recognized adaptations to counter autophagy [28–30]. Possibly, a best molecularly defined example of the interference of intracellular bacteria with autophagy is the injection of a protease RavZ that enzymatically incapacitates lipidation of mAtg8 factors [31] described here in the later sections dealing with the autophagy subsystems. The existence of countermeasures in microbes directed at interference [28] or even exploitation of autophagy by certain microbes [32] further underscores the significance of autophagy as an innate defense mechanism with which pathogens have to contend.

AUTOPHAGIC CONTROL OF M. tuberculosis AND RECENT CONTROVERSIES

The prolonged neutrophilic response in autophagy-deficient animals and its role in pathology in mouse models of tuberculosis, first reported by Castillo et al. [19] and Watson et al. [20], have been confirmed in a recent study [23]. The latter study provides an in-depth, invaluable follow-up and raises additional important questions [23] to be subjects of future studies. First, this study reported data that the neutrophil phenotype may be independent of autophagy [23]. Nevertheless, ex vivo studies by others (Deretic and coworkers [19]) have demonstrated that excessive IL-1 activation by autophagy-deficient macrophages leads to Th17 polarization as a likely contributor to neutrophil-associated effects in vivo. This is in keeping with reports by numerous groups regarding the excess IL-1 activation secondary to loss of autophagy function observed both in vitro and in vivo in various models of inflammatory disease [33–35].

Furthermore, Kimmey et al. [23] reported data, and others [36] interpreted them as an indication that autophagy, as a pathway, may not matter for control of M. tuberculosis. Such proposals call for further investigations. Of relevance is that the above studies covered only the early stages of M. tuberculosis infection in a mouse model, whereas the modeling of tuberculosis infection in mice (that inherently control M. tuberculosis far better than humans) requires observations well beyond the early 80 d covered in the study in question [23]. As a contemporary illustration of this issue, one may want to consider the recently reported negative findings with cGAS when M. tuberculosis infection was monitored for only 100 d [37], whereas positive (albeit surprising data) on cGAS and control of M. tuberculosis have been reported in a simultaneously published study extending past the first 100 d of infection [38]. It should also be understood that the claims made as autophagy being insufficient to control M. tuberculosis [23, 36] may be limited to basal autophagy. In this context, it is relevant to recall that the initial studies showing the role of autophagy in defense against M. tuberculosis were based entirely on induced autophagy and not on its basal levels [15]. Furthermore, the inability of basal autophagy to suppress M. tuberculosis is potentially explained by the ability of M. tuberculosis to suppress innate levels of autophagy [39–45]. Most recent studies extend the repertoire of anti-autophagic mechanisms possessed by M. tuberculosis, showing that infection with the tubercle bacillus reprograms autophagy via microRNA-33 induction [46]. These considerations bring us back full circle where we started, underscoring the need for pharmacological intervention to induce autophagy [15]. This is important from a translational standpoint if the therapeutic potential of autophagy is to be realized in control of tuberculosis; such efforts are underway [47, 48].

AUTOPHAGY PATHWAY

The role of autophagy in cellular physiology exceeds its immune functions. It maintains energy and nutrient homeostasis, carries out organellar repair or elimination when needed, and is among the key intracellular quality control processes of the eukaryotic cell [7, 49–51]. The sensu stricto form of autophagy (the only type covered herein and also known as “macroautophagy”) is a defined pathway dependent on conserved ATG proteins [52]. During autophagy, the cytoplasmic cargo is typically sequestered into specialized endomembranous organelles, termed autophagosomes, distinguished by a “popular” marker called LC3, which is 1 of the 6 mAtg8 homologs [53]. These organelles fuse with lysosomal compartments to form autolysosomes, where the captured material is degraded or otherwise processed [52], although functionally different terminations of the pathway are possible, such as secretion [54–56], reviewed recently elsewhere [57]. We cover here only the canonical autophagosomal pathway, terminating with autolysosomal organelles and cargo degradation. The core autophagy machinery in mammalian cells has several seemingly independent subsystems (Table 1), dissected in sections below. These subsystems are interconnected via specific molecular interactions into a unifying apparatus (Fig. 1).

TABLE 1.

Autophagy subsystems

Subsystem	ATG and other components	Function	Notes	References
Regulatory Ser/Thr protein kinases and phosphatases	ULK1, AMPK, MK2, mTOR, calcineurin	Upstream kinases regulating activation of the VPS34-Beclin 1-ATG14L system; phosphatases regulating TFEB	ULK1 (mAtg1 ortholog) is the first autophagy pathway-dedicated protein kinase; mTOR and AMPK provide nutrient and energy inputs; MK2 transduces stress signals; mTOR phosphorylates TFEB; and calcineurin dephosphorylates it to transcriptionally activate the autophagy-lysosomal system.	[89–93, 102]
Lipid kinases and PI3P production	VPS34, Beclin 1, ATG14L	Localized PI3P generation leading to autophagosomal membrane biogenesis	ATG14L also connects with autolysosomal fusion via syntaxin 17.	[14, 83–85, 88]
PI3P recognition and recruitment of other ATG factors	WIPI2, DFCP1	Connecting spatially PI3P production with building of autophagosomal membrane	WIPI2 binds both PI3P and ATG16L1, thus connecting PI3P production with mAtg8 conjugation. DFCP is a marker.	[14, 95]
Autophagosomal membrane identity and formation	mAtg8s: LC3A, LC3B, LC3C, GABARAP, GABARAPL1, GABARAPL2	Roles in autophagic membrane biogenesis, closure, and cargo capture	LC3B used as autophagosome marker; GABARAPs scaffolding other ATG factors and cargo receptors	[76–79, 81, 132, 133, 141]
Membrane addition	ATG9	In yeast, cooperation with Atg1 complex in pre-autophagosomal structure formation	Addition of new membrane to nascent phagosomes	[162–165]
“E3 ligase-like” system for mATG8 lipidation	ATG3, ATG4, ATG5, ATG7, ATG10, ATG12, ATG16L1	Conjugation system for lipidation of mATG8	ATG16L1 plays a central role in connecting mAtg8 lipidation with PI3P production through binding to WIPI2 and also connects with ULK1 via FIP200.	[94–98]
Autophagosome-lysosome fusion	Syntaxin 17, ATG14L	Control and execution of autophagosome-lysosome fusion	SNARE-mediated fusion between autophagosomes and lysosomes (syntaxin 17-SNAP29-VAMP8); ATG14L regulates syntaxin 17.	[87, 88]
SLRs	NDP52, TAXBP1, NBR1, optineurin, TOLLIP	Receptors recognizing tags (ubiquitin or galectin) on cargo	Binding to ubiquitin or galectin on cargo and to LC3 on autophagic membrane	[24, 125–128, 130]
Receptor-regulators	TRIM5, TRIM20, TRIM21	Precision autophagy	Coupling of cargo recognition with recruitment and activation of ULK1, Beclin 1, and other ATGs	[132, 133, 141]
Other receptors	FUNDC1, Bcl-2-L-13, Nix, BNIP3, SMURF1, FAM134B, NCOA4	Unique receptors thus far implicated in autophagy of different substrates	Receptors not falling into above categories (SLRs, receptor-regulators)	[59, 124, 135–140]
Assembly platforms	Exo84, IRGM	Coalescence of autophagy factors coupled with stimuli or cargo recognition	Exocyst, TRIMosome	[108, 132, 133, 142]
			IRGM platform
Ubiquitin ligases category I	AMBRA1	Regulatory (promoting autophagy)	ULK1, Beclin 1, IRGM	[105–108]
	TNFR-associated factor 6
Ubiquitin ligases category II	Cullin3-KLHL20, Nedd4	Regulatory (inhibiting autophagy)	De-stabilization of positive regulators (VPS34, Beclin 1, ULK1, ATG14L, AMBRA, ATG4B, DEPTOR) and stabilization of negative regulators (Bcl-2)	[109–117]
	RNF216
	ZBTB16-Cullin3-Roc1
	RNF2, DDB1/Cullin4
	RNF5
	SCF, Cullin5
	Parkin
Ubiquitin ligases category III	Parkin, LRSAM1, SMURF1	Targeting (placing ubiquitin tags on autophagic cargo)	Mitophagy, xenophagy	[21, 118–124]
Coordination between autophagosomal and lysosomal systems via transcriptional control	TFEB, MiT/TEF	TFEB translocates from the cytoplasm to the nucleus to coactivate autophagy and lysosomal expression	TFEB and other MiT/TEF couple mTOR-nutrition and calcineurin-Ca2+ sensory systems on lysosomes with expression of autophagosomal/lysosomal systems	[100–104]

DFCP1, Double FYVE domain-containing protein 1.

Figure 1. Autophagy pathway with its regulatory and execution subsystems.

Depicted are the simplified conventional views of canonical macroautophagy organelles and pathway with different subsystems detailed in Table 1. Ω, Omegasome, a PI3P-positive structure on the ER believed to provide a cradle for formation of phagophores positive for mAtg8 orthologs (e.g., LC3-PE, also known as LC3-II). Phagophores enwrap the cargo, enlarge, and close to form double-membrane autophagosomes that then fuse with lysosomes to form autolysosomes, where the captured cargo is degraded. Cargo is brought into the phagophores via receptors that recognize cargo through binding to tags, such as ubiquitin, placed on the cargo by E3 ubiquitin ligases (category III; see Table 1). Protein kinases, lipid kinases, and assembly platforms (detailed in Table 1) drive the formation of autophagosomes. These are regulated by E3 ubiquitin ligases that either stabilize (category I) or destabilize (category II) them. The entire system is regulated by signals that can be immunologic, nutritional, differentiation in nature, or from various stressors. Lysosome is not just a passive contributor of lysosomal contents but also works as a sensory organelle that relays the status to the nucleus, whereby autophagosomal and lysosomal biogenesis are coordinated at the transcriptional level.

Among many cytoplasmic targets of autophagy are mitochondria (the process being termed “mitophagy” [7], protein aggregates (“aggrephagy”) [58], ER (“ER-phagy”) [59], lipid droplets (“lipophagy”) [60], lysosomes (“lysophagy”) [61], and invading microbes (“xenophagy”) [29] (Fig. 1). The relationships between autophagosomes and membranous compartments, such as ER, mitochondria, and lipid droplets/neutral lipid stores, are complex, and whereas autophagy consumes these as targets through lysosomal degradation, these organelles also contribute membranes or lipids as sources for formation and growth of newly formed autophagosomes [49, 62–65].

Autophagy is active in all eukaryotic cells, and in mammals, it can play both nutritional and cytoplasmic quality control roles, which is of relevance for function and survival of nearly all cells. Although autophagy has been considered on and off a type of programmed cell death, it is now primarily appreciated as a programmed cell survival [66], with some potential crossover connections with cell death [67, 68]. With such broad fundamental roles, autophagy affects both the functionality and pathology, exerted through numerous cell types, including leukocytes. This is reflected in its role in cancer, where it is proposed to prevent tumorigenesis [69], but also sustains growth of established tumors [70], myodegeneration, and muscle wasting. Autophagy can also be associated with cancer-related cachexia [71]; loss of muscle stem cell-regenerative capacity in aging [72]; metabolic diseases (including type II diabetes [73] that may include role of autophagy in myeloid cells [74]); neurodegeneration [51]; inflammatory disorders, such as Crohn’s disease; and numerous other pathologic states [75].

AUTOPHAGY CORE SUBSYSTEMS

The 6 mAtg8 homologs (LC3A, -B, and -C, GABARAP, and GABARAPL1 and -2), are C-terminally lipidated with PE, a process facilitated by the ATG5–ATG12/ATG16L1 E3 ligase-like system. The lipid modification enables the membrane association of mAtg8 [76]. Different mAtg8s may play distinct roles in autophagosomal membrane biogenesis [77]. Moreover, mAtg8s also bind and scaffold other ATG factors, including ULK1 [78, 79] (one of several mAtg1 paralogs [80]) and autophagy cargo receptors [81].

As already introduced, PI3P production is key for autophagy [13, 14], albeit another monophosphoinositide (PI5P) has recently been suggested to play a role, especially during glucose starvation [82]. The production of PI3P is accomplished through the action of the PI3K VPS34 complex containing Beclin 1 [83] and ATG14L [84]. ATG14L confers membrane curvature preferences upon VPS34, compatible with autophagosomal formation [85, 86]. ATG14L also interacts with a key SNARE, syntaxin 17, of significance for autophagosome formation and maturation [65, 87, 88]. The production of PI3P occurs on membrane precursors yielding nascent autophagosomes [14].

The Ser/Thr kinase ULK1 phosphorylates and activates Beclin 1 [89], along with other kinases, such as MK2 [90] and AMPK [91]. The nutritional and possibly other signals are transmitted via AMPK, which positively regulates ULK1 [92], and via mTOR, which phosphorylates ULK1 on inactivating regulatory sites [92, 93].

The linchpins connecting the above systems are WIPI2 and ATG16L1. WIPI2 recognizes PI3P (the product of the human VPS34-Beclin 1-ATG14L complex) on membranes, whereas it also interacts with ATG16L1, a key component of the mAtg8/LC3 lipid conjugation system [94], thus spatially connecting LC3 conjugation with PI3P production [95]. ATG16L1 is also a binding partner for FIP200, a component of the ULK1 complex [95–98], ensuring that all core subsystems are coming together (Table 1 and Fig. 1).

Final steps of autophagy include fusion of autophagosomes with lysosomes to form autolysosomes [99]. Autophagy is transcriptionally coordinated with lysosomal biogenesis via TFEB and other MiT/TEF factors [100–104]. At the membrane-trafficking level, among other processes, syntaxin-17 [87], in cooperation with ATG14L [88], authorizes fusion between autophagosomes and lysosomes, leading to formation of autolysosomes, where the cargo is degraded (Table 1 and Fig. 1).

UBIQUITIN LIGASES AND AUTOPHAGY

Autophagy interacts with the ubiquitin system. These overlaps can be classified into 3 major categories (Table 1): 1) category I refers to ubiquitination as a positive regulator (often through stabilization) of autophagy factors. Ubiquitination can stabilize Beclin 1 [105, 106], ULK1 [107], and IRGM [108] to promote autophagy. 2) Category II, by far the most numerous, refers to E3 ubiquitin ligases and ubiquitination, acting to down-regulate autophagy through proteasomal degradation of Beclin 1 [109–111], ULK1 [111], ATG14L [111, 112], ATG4B [113], and AMBRA [114, 115], stabilizing Bcl-2 [116], a negative regulator of Beclin 1, or destabilizing the negative regulator of mTOR DEPTOR [114, 117]. 3) Category III refers to cargo targeting [50]. This includes the well-established case of the Pink 1–Parkin system in mitophagy. Parkin is the E3 ligase, which is activated by Pink 1-dependent phosphorylation of the ubiquitin-like domain within Parkin and ubiquitin, conjugated to targets [118–122]. Parkin has also been implicated in M. tuberculosis control by autophagy [20, 21]. Two additional E3 ligases, LRSAM1 in autophagy of Salmonella [123] and SMURF1 in autophagy of the Sindbis virus capsid [124], have been reported.

SELECTIVE AUTOPHAGY: SLRs, TRIMs, AND OTHER UNIQUE RECEPTORS

Autophagy can be bulk or selective. During the latter, selective form of autophagy, the cargo to be captured by the autophagosomes is modified with tags, such as galectins [7, 125], ubiquitin (category III described above) [50], or phosphorylated ubiquitin [120]. These tags can then be recognized by SLRs [28, 81]. The founding member of SLRs is sequestosome 1 (commonly referred to as p62) [126]. SLRs include NDP52, TAXBP1, NBR1, and optineurin [24, 125–129]. SLRs bind both to mAtg8s through their LC3-interacting motifs and to ubiquitin via a variety of ubiquitin-binding domains (e.g., ubiquitin binding in ABIN and NEMO domain, ubiquitin-associated domain, ubiquitin-binding zinc finger) [50]. TOLLIP, the most recently described SLR, binds to ubiquitin and LC3 [130].

There are close to 80 TRIMs in humans and at least one subset of them acts as selective autophagy receptors. The TRIM protein family [131] members contain N-terminal RING domain, B-box domains, a coiled-coil domain, and a C-terminal domain, such as SPRY, involved in binding to autophagic cargo [132, 133]. TRIM5, TRIM20, and TRIM21 bind mAtg8s [132, 133], while recognizing cargo via their SPRY (TRIM5, TRIM21) or Pyrin (TRIM20) domains. TRIM5 recognizes viral capsids within the retroviral core and delivers the capsid protein p24 (CA) for degradation [134]. TRIM20 is a selective autophagy receptor for the inflammasome components, procaspase 1, NLRP1, and NLRP [132]. TRIM21 is a selective autophagy receptor for the dimerized (activated) form of IFN regulator factor 3, a transcriptional activator of the type I IFN response [132].

Unique autophagy receptors, not belonging to SLRs or TRIMs, also exist. In addition to SLRs [129], several unique autophagy receptors work in mitophagy: FUNDC1 [135], Bcl-2-L-13 [136], Nix [137], BNIP3 [138] and SMURF1 [124]. ER-phagy is carried out by FAM134B [59]. NCOA4 is a receptor for autophagy of ferritin [139, 140].

PLATFORMS FOR AUTOPHAGY APPARATUS ASSEMBLY

The TRIM proteins, in addition to their function as autophagic receptors, also function as platforms for assembly of autophagy factors, including Beclin 1, ULK1, and mAtg8s [132, 133]. Their double duty as regulators and receptors has lead to the concept of "precision autophagy" [132, 141], whereby the same entity, e.g., TRIM, which recognizes autophagic substrate, also assembles autophagy machinery. This type of autophagy occurs only at the location where it is needed by coupling cargo recognition with a localized activation of autophagy apparatus.

Other proteins or protein complexes have been implicated in assembly of autophagy machinery in mammalian cells. For example, exocyst, a multicomponent complex, may scaffold starvation-induced autophagy [142], whereas IRGM (see below for more details) acts as a platform for assembly of ULK1, Beclin 1, and ATG16L1 in response to the presence of microbial products [108].

COUPLING BETWEEN INNATE IMMUNITY RECEPTORS AND AUTOPHAGY: THE NOD2-IRGM-ATG16L1 EXAMPLE

Autophagy responds to endogenous danger-associated molecular patterns and microbial products commonly referred to as PAMPs [5]. Autophagy triggered by these agonists can eliminate microbes through a process termed xenophagy or can control inflammation and other immune processes [5, 27]. Connections among PRRs, TLRs, cGAS, receptor-interacting serine/threonine–protein kinase 2, NLRs, etc., have been established and reviewed [5, 27, 28]. Among the more recently delineated systems explaining how recognition of PAMPs via PRRs results in activation of autophagy is the NOD2-IRGM-ATG16L1 complex [108]. Polymorphisms in the NOD2, ATG16L1, and IRGM genes all confer risk for Crohn’s disease [143–146], whereas polymorphisms in IRGM are associated with a risk for active tuberculosis [147, 148].

It has been known that ATG16L1 and NOD2 interact [149, 150], placing these 2 of the Crohn’s disease genetic risk factors together, but until recently, IRGM was not firmly linked to these factors. A complicating factor in understanding the exact function of IRGM has been that it is a distinctly human gene [151], with orthologs present only in African great apes and active alleles absent in the ancestral lineages [151]. The mouse has 21 IRG genes, as opposed to the distantly related single IRGM gene in humans, encoding a Ras-sized, 21 kDa protein. However, the prevailing past view of the murine IRGs (which all encode 40 kDa proteins) is that they have predominantly nonautophagy functions [152]. Nevertheless, this remains to be examined further, as mutant mice with inactivated Irgm1 (the presumed closest mouse homolog of human IRGM [151, 153]) also show an inflammatory bowel disease phenotype, along with the ATG16L1 hypomorph [154] or knockout mice [33], as well as the NOD2 mutant mice [155]. However, the latest studies indicate that murine Irgm1 [156] causes mitochondrial fission, similarly to human IRGM [157, 158], and that as in the case of IRGM controlling autophagy [157], Irgm1 affects autolysosomal processing [159].

As mentioned in the subsection on autophagy platforms, IRGM interacts with key autophagy regulators, ULK1, Beclin 1, ATG14L, and ATG16L1 [108]. Colocalization in cells between IRGM and ATG16L1 upon NOD2 activation on M. tuberculosis-harboring phagosomes has been observed by independent studies [160], in keeping with the previously reported NOD2–ATG16L1 colocalization in control of microbially stimulated autophagy [149, 150]. Furthermore, IRGM interacts with NOD2 and physically links NOD2 and other microbial sensors (such as NOD1 and a subset of TLRs) with the core autophagic apparatus assembled on IRGM as a platform [108]. These findings clarify how IRGM works. Nevertheless, as a cautionary note, ATG16L1 has been reported to have a genetically separable autophagy-independent function in suppressing inflammation [161], and thus, the above factors likely play multifactorial roles.

CONCLUSIONS

Autophagy is significant, both as a fundamental intracellular homeostatic pathway and as an antimicrobial and anti-inflammatory process of particular significance for leukocyte function. Recent advances have revealed how core autophagy factors become organized in subsystems and how these subsystems come together into a fully functional unit. Furthermore, we now know how these parts are coupled with immune signaling. The number of autophagy receptors and platforms for assembly of the autophagic apparatus in mammalian cells is growing and suggests versatility while increasingly emphasizing selectivity. The function of these systems in leukocytes deserves continuing in-depth attention and may provide unique opportunities for physiologic, immunologic, and pharmacological intervention in infectious and inflammatory diseases.

AUTHORSHIP

V.D. conceived of the review, analyzed the literature, wrote the text, and created the table and figure.

Glossary

AMBRA1

autophagy and coiled-coil, moesin-like B-cell lymphoma 2-interacting protein regulator 1

AMPK

AMP-activated protein kinase

ATG

autophagy-related protein

Bcl-2

B-cell lymphoma 2

Bcl-2-L-13

Bcl2-like 13

Beclin 1

coiled-coil, moesin-like B-cell lymphoma 2-interacting protein

BNIP3

B-cell lymphoma 2 and adenovirus E1B 19 kDa-interacting protein 3

cGAS

cyclic GMP-AMP synthase

DEPTOR

domain containing mammalian target of rapamycin-interacting protein

ER

endoplasmic reticulum

FAM134B

family with sequence similarity 134 member B

FIP200

focal adhesion kinase family interacting protein of 200 kDa

FUNDC1

FUN14 domain-containing 1

GABARAP

GABA receptor-associated protein

GABARAPL1/2

GABA receptor-associated protein-like 1/2

IRGM

immunity- related GTPase M

LC3

microtubule-associated protein 1A/1B-light chain 3

LRSAM1

leucine-rich repeat and sterile alpha motif containing 1

mAtg8

mammalian autophagy-related protein 8 protein (microtubule-associated protein 1A/1B-light chain 3A, -B, -C, GABA receptor-associated protein, -like 1, -like 2)

MiT/TEF

microphthalmia/transcription factor E family

MK2

MAPK-activated protein kinase 2

mTOR

mammalian target of rapamycin

NBR1

neighbor of BRCA1 gene 1

NCOA4

nuclear receptor coactivator 4

NDP52

nuclear dot protein 52 kDa

Nix/BNIP3L

BCL2 and adenovirus E1B 19-kDa interacting protein 3-like

NLRP

nucleotide-binding oligomerization domain-containing protein-like receptor protein

NOD

nucleotide-binding oligomerization domain-containing protein

PAMP

pathogen-associated molecular pattern

PE

phosphatidylethanolamine

PI3P

phosphatidylinositol 3-phosphate

Pink 1

phosphatase and tensin homolog-induced kinase 1

PRR

pattern recognition receptor

SLR

sequestosome 1/p62-like receptor

SMURF1

drosophila mothers against decapentaplegic protein-ubiquitination-related factor 1

SNARE

soluble N-ethylmaleimide-sensitive factor attachment protein receptor

SPRY

Spla and the ryanodine receptor domain

TAX1BP

T cell leukemia virus type I-binding protein

TFEB

transcription factor EB

TOLLIP

Toll-interacting protein

TRIM

tripartite motif family of proteins

ULK

Unc-51-like autophagy activating kinase

VPS34

vacuolar protein sorting 34

WIPI2

WD repeat domain phosphoinositide-interacting protein 2

DISCLOSURES

The author declares no conflicts of interest.