: An Emerging Immunological Paradigm Vojo Deretic Autophagy is a fundamental eukaryotic process with receptors (PRRs); 3) regulation of inflammasome activation multiple cytoplasmic homeostatic roles, recently ex- and alarmin secretion; and 4) cytoplasmic Ag processing for panded to include unique stand-alone immunological MHC II presentation and T cell homeostasis. We relate these functions and interactions with nearly all parts of the processes to conventional immunological functions, defense immune system. In this article, we review this growing against infectious agents, chronic inflammatory diseases, and repertoire of autophagy roles in innate and adaptive im- other immunological disorders. munity and inflammation. Its unique functions include cell-autonomous elimination of intracellular microbes Autophagy pathway facilitated by specific receptors. Other intersections of The key morphological features of autophagy are endomem- autophagy with immune processes encompass effects branous organelles, called autophagosomes (Fig. 1), whose on inflammasome activation and secretion of its sub- formation is controlled by the autophagy-related gene (Atg) strates, including IL-1b, effector and regulatory inter- and additional factors comprehensively reviewed elsewhere actions with TLRs and Nod-like receptors, Ag pre- (1). Briefly, the Atg system includes Ser/Thr kinases Ulk1 and sentation, naive T cell repertoire selection, and mature Ulk2 (Atg1), Beclin 1 (Atg6; a subunit of the class III PI3K T cell development and homeostasis. Genome-wide as- human vacuolar protein sorting 34 [hVPS34 complexes]), sociation studies in human populations strongly impli- Atg5–Atg12/Atg16L1 complex, and microtubule-associated cate autophagy in chronic inflammatory disease and protein L chain 3s (LC3s) (multiple Atg8 orthologs), with LC3B being a commonly used marker for identification of autoimmune disorders. Collectively, the unique fea- autophagosomes (1). Ulk1/2 and Beclin 1-hVPS34 integrate tures of autophagy as an immunological process and upstream signals and direct the downstream Atg conjugation its contributions to other arms of the immune sys- cascade, which involves Atg5–Atg12/Atg16L1 assembly as an tem represent a new immunological paradigm. The “E3 enzyme” for LC3 lipidation. Lipidated LC3s in con- Journal of Immunology, 2012, 189: 15–20. junction with other factors assemble, elongate, and close na- scent autophagic organelles. Autophagosomes interact with by guest on October 1, 2021. Copyright 2012 Pageant Media Ltd. n this Brief Review, we cover the immunological roles of endosomal and lysosomal organelles to mature into autoly- macroautophagy (1), a specific autophagic process that sosomes (1) or promote unconventional secretion of cyto- I will be referred to herein as sensu stricto autophagy or plasmic constituents, as first demonstrated in yeast (3) and simply autophagy. Autophagy is unique in its capacity to recently shown to include immune mediators (4, 5). In ad- sequester, remove, or process bulk cytosol, cytoplasmic or- dition to its immunological functions (2), autophagy plays ganelles (1), invading microbes, and immunological media- a general cellular homeostatic role by supplying nutrients tors (2), as depicted in Fig. 1. Another special property (e.g., amino acids) through cytosol autodigestion at times illustrated in Fig. 1 is that autophagy acts as a topological of starvation or growth factor withdrawal, and serves as a

http://classic.jimmunol.org inverter—bringing molecules and objects from the cytosolic quality and quantity control mechanism for intracellular or- side to the luminal side for degradation or processing, inter- ganelles (1). action with luminal receptors, or secretion from cells. In this At the transcriptional level, regulation of autophagy is review, we discuss the four principal manifestations of im- coupled to the lysosomal system via TFEB (6) and other munological autophagy (Fig. 1): 1) direct pathogen elimi- proteolytic systems via FoxO3A (7). However, autophagy is nation assisted by sequestosome 1-like receptors (SLRs); 2) primarily a rapid-response remodeling of membranes that

Downloaded from regulation and effector functions of pattern recognition occurs in the cytoplasm under the control of signaling systems

Department of Molecular and , University of New Mexico lecular pattern; GWAS, genome-wide association study; HMGB1, high-mobility group Health Sciences Center, Albuquerque, NM 87131 protein B1; hVPS34, human vacuolar protein sorting 34; IKK, inhibitor of NF-kB kinases; IRGM, immunity-related GTPase M; LC3, microtubule-associated protein L Received for publication April 17, 2012. Accepted for publication May 2, 2012. chain 3; NDP52, nuclear domain 10 protein/Ag nuclear dot 52 kDa protein; NLR, This work was supported by National Institutes of Health Grants AI042999, AI069345, nucleotide binding and oligomerization domain-like receptor; PAMP, pathogen- and ARRA RC1AI086845; Crohn’s & Colitis Foundation of America Grant CCFA2053; associated molecular pattern; PRR, pattern recognition receptor; RLR, RIG-I–like re- and a Bill and Melinda Gates Grand Challenge Explorations grant. ceptor; ROS, reactive oxygen species; SLR, sequestosome 1/p6-like receptor; TAK1, TGF-b–activated kinase 1. Address correspondence and reprint requests to Dr. Vojo Deretic, Department of Mo- lecular Genetics and Microbiology, University of New Mexico Health Sciences Center, Ó 915 Camino de Salud NE, Albuquerque, NM 87131. E-mail address: vderetic@salud. Copyright 2012 by The American Association of Immunologists, Inc. 0022-1767/12/$16.00 unm.edu Abbreviations used in this article: AMPK, AMP-activated protein kinase; Atg, autophagy-related gene; CD, Crohn’s disease; DAMP, danger/damage-associated mo-

www.jimmunol.org/cgi/doi/10.4049/jimmunol.1102108 16 BRIEF REVIEWS: AUTOPHAGY AS AN IMMUNOLOGICAL PARADIGM by guest on October 1, 2021. Copyright 2012 Pageant Media Ltd.

http://classic.jimmunol.org FIGURE 1. The four principal manifestations of immunological autophagy. (1) Direct pathogen elimination assisted by SLRs and DAMP receptors. (A) Invading microbes either escaping the endosomes or phagosome (thin outline) or remaining in phagosomes that can be partially permeabilized (dotted outline) are captured by and SLRs that recognize tags such as ubiquitin (small red circles) or diacylglycerol and b-galactoside (not shown) on damaged host membranes. The captured microbes or those cocaptured with the earmarked membranes are delivered into autophagic organelles (thick outline), starting with phagophores (crescents), progressing through autophagosomes (full white circles), and ending in degradative autolysosomes (full pink circles). SLRs possess an LC3 interacting region (LIR), phosphorylation sites (black dot, arbitrarily positioned), and a tag recognition domain (UBA, depicted for p62). Galectins (hatched square), considered to be DAMP receptors, have carbohydrate recognition domains (not shown) that recognize sugars on glycans exposed on the endofacial

Downloaded from lumenal membrane leaflet of permeabilized organelles. (B) Alternatively, autophagy can sequester cytosolic proteins such as ubiquitin and ribosomal proteins (pear-shaped tan-colored shapes, ribosomes) and digest them into antimicrobial peptides (AMPs) that can be delivered to pathogens confined in phagosomes. (C) SLRs can engage in proinflammatory signaling via TRAF6 (shown) or atypical PKC (not shown), for example, or promote cell death by activating caspase-8 through aggregation (not shown). (2) PRR regulation and effector functions. (A) Autophagy can be activated downstream of TLR signaling upon recognition of PAMPs (X’s). (B) As a topological inverter device, autophagy can deliver cytosolic PAMPs to the lumen of endomembranous organelles, where they can interact with the receptor portions of TLRs. Known functional interactions with NLRs and RLRs are summarized by positive (arrows) and negative (lines symbolizing inhibition) effects. (3) Inflammasome regulation and secretion of alarmins. Autophagy plays a dual role in controlling inflammasome output: It suppresses basal levels of inflammasome activation but also assists IL-1b and IL-18 release from the cells via an autophagy-dependent unconventional secretory pathway [(A); autosecretion]. Inflammasomes, heteromeric protein assemblages (consisting of ASC, caspase 1, and NLRP3 or AIM2) act as platforms for activation in response to K+ efflux or presence and action of DAMPs (silica, crystal-like shape). ROS and mtDNA can be released as endogenous DAMPs by damaged mitochondria if they are not continuously removed by autophagy. This results in caspase-1 activation and proteolytic processing of proforms of proinflammatory cytokines (IL- 1b). Whereas autophagy lowers the sources of endogenous DAMPs by disposing of depolarized (DCm) or leaky mitochondria (sources of ROS and mtDNA), autophagy also enables secretion of cytosolic IL-1b (and other alarmins such as HMGB1) during the very early stages of physiological inflammasome activation in response to exogenous DAMP sources (microbial or sterile). Autosecretion (autophagy-based unconventional secretion; see text for explanations) enables ex- tracellular release of cytosolic proteins such as IL-1b and HMGB1 per the illustrated process controlled by Atg factors and GRASP (see text). Autosecretion occurs early in the process of stimulation and is swamped pre- or shortly poststimulation by the anti-inflammatory effects of autophagy. The (Figure legend continues) The Journal of Immunology 17

faster than transcriptional changes. The classical nutritional/ virus interacts with p62 (25). Candidate E3 ligases contrib- energy regulation of autophagyisviamTORandAMP- uting to target ubiquitination have been identified in some activated protein kinase (AMPK) inhibiting and activating, instances: SMURF1 for sindbis virus (26) and LRSAM1 as respectively, Ulk1/2 (1). This pathway merges with signaling a candidate for Salmonella (27). via the inhibitor of NF-kB kinases (IKK), frequently involved The most recent player in these processes is 8, a in immune signaling. IKKa and IKKb transduce the classical cytosolic lectin binding to b-galactoside glycans. The mem- signal for autophagy induction—starvation (8)—but this sig- brane glycans are normally present only on the luminal side of naling is not based on nuclear NF-kB responses. Instead, IKK parasitophorous vacuoles. However, upon membrane damage and AMPK signaling merge via TGF-b–activated kinase 1 the glycans come in contact with the cytosol and thus become (TAK1) and its activators TAB2 and TAB3. Upon autophagy recognized by cytosolic galectins (21) (Fig. 1, panel 1, hatched induction, TAB2 and TAB3 dissociate from and thus activate square). Galectin 8 is important in restricting Salmonella Beclin 1 and also bind to and activate TAK1 (8), whereas proliferation, and plays an early role until supplanted by a TAK1 in turn phosphorylates and activates AMPK. phase dominated with ubiquitin and ubiquitin-recognizing In T cells, autophagy is activated upon TCR engagement SLR—NDP52. It appears that the phases and the sequence and CD28 costimulation and supports their effector func- of recognizing membrane damage could be ushered in by the tions and proliferation (9). Recently, class III PI3K hVPS34 appearance of diacylglycerol (28), followed by galectin-b– was found to be dispensable for autophagy induction in galactoside recognition, followed by NDP52–ubiquitin rec- T cells, albeit required for T cell homeostasis via its regula- ognition. Because galectin 8 and NDP52 interact, a sequential tion of receptor endocytosis (10), bringing up the possibility action is doubly ensured. Galectin 8 is important for the re- of alternative pathways in PI3P signaling, as suggested by the cruitment of NDP52, as the requirement for galectin 8 to positive role of class I PI3K p110b (11). restrict Salmonella proliferation could be bypassed by ex- Innate immune signaling can induce autophagy. TRAF6 pressing a fusion hybrid between galectin 3 and NDP52. downstream of TLR4 activates autophagy (12). Alarmins or Galectin 3 per se is not required for restriction, although it is damage-associated molecular patterns (DAMPs) induce auto- found on Salmonella vacuoles, primarily because it, unlike phagy (13, 14). High-mobility group protein B1 (HMGB1), galectin 8, cannot interact with NDP52. Galectin 8 recog- an alarmin, undergoes translocation from the nucleus into the nizes host membrane glycans and, indirectly, Salmonella car- cytoplasm and then out of the cells by unconventional se- bohydrates, albeit it can directly recognize blood group B- cretion (5, 15) or cell death-associated release, inducing auto- positive E. coli O86. Galectin 8 is also important for Shi- phagy at each stage: cytoplasmic through de-repression gella and Listeria, and can even detect sterile damage to en- of Beclin 1 by displacing its negative regulator Bcl-2, or ex- dosomes and . tracellularly via RAGE signaling(13,14).Inadditionto SLRs can also act in a completely different manner to HMGB1, DAMPs such as ATP, IL-1b, and DNA com- promote autophagic killing of intracellular microbes (Fig. 1, plexes are known to induce autophagy (reviewed in Ref. panel 1, right). They gather cytoplasmic proteins (e.g., ubiq- by guest on October 1, 2021. Copyright 2012 Pageant Media Ltd. 16). uitin and ribosomal proteins) to be converted in autolyso- somes into antimicrobial products that, upon delivery to cy- Autophagy in direct pathogen elimination toplasmic compartments harboring microbes, transform them From an evolutionary perspective, the most primal manifes- into autophagolysosomes, organelles with enhanced antimi- tation of immunological autophagy is direct capture and crobial capacities relative to conventional phagolysosomes degradation of invading intracellular microbes by autophagy (29–31). (Fig. 1, panel 1, left). This cell-autonomous defense function of autophagy is often countered by microbial adaptation Autophagy and pattern recognition receptors http://classic.jimmunol.org mechanisms, and a number of highly adapted pathogens can Autophagy interacts with classical PRRs, including TLRs, convert autophagic organelles into growth-supporting com- Nod-like receptors (NLRs), and RIG-I–like receptors (RLRs). partments (17). Autophagic capture of intracellular microbes TLRs and autophagy intersect in two ways, illustrated in Fig. is facilitated by autophagic adaptors, referred to as seques- 1, panel 2. First, autophagy is an effector mechanism (e.g., tosome 1/p62-like receptors (SLRs) (18). SLRs have LC3 elimination of microbes illustrated in Fig. 1, panel 1)down- interacting regions and cargo-tag (e.g., ubiquitin) recognition stream of TLR activation. TLR4 triggers autophagy via Downloaded from domains and are modulated by protein kinases. Salmonella TRAF6 E3 ligase, ubiquitination of Beclin 1, and Bcl-2 dis- requires multiple SLRs [p62, nuclear domain 10 protein/Ag sociation from the BH3 domain of Beclin 1 (12). Second, nuclear dot 52 kDa protein (NDP52), optineurin] (19, 20), autophagy as a topological inverter device can bring cytosolic phosphorylation of at least one of the SLRs (optineurin) with pathogen-associated molecular pattern (PAMP) molecules an IKK-related kinase, TBK-1 (20), and an intracellular into the lumen, where they can bind the ligand recognition DAMP receptor (galectin 8) (21). The SLRs p62 and NDP52 side of the TLR. This has been demonstrated for TLR7 (32), are also engaged in clearance of Shigella and Listeria (22–24), TLR4 ligands (33), and TLR9 in the context of BCR sig- whereas streptococci are affected by NDP52 (19). Sindbis naling (34).

latter keep the tonic levels of inflammasome activation low and bring them back to resting levels following stimulation. (4) Cytosolic Ag processing for Ag presentation. Autophagy assists as a topological inversion device in delivery of cytosolic (and nuclear) proteins to MHC II processing and presentation com- partments. Explanations in the text include relationships to selection of naive T cell repertoires and citrullination of Ags. AP, Autophagy; mtDNA, mitochondrial DNA; ROS, reactive oxygen species. 18 BRIEF REVIEWS: AUTOPHAGY AS AN IMMUNOLOGICAL PARADIGM

NLR and autophagy interactions are evolutionarily con- stasis, and is essential for T cell survival following exit from served from Drosophila (35) to humans (16). Nod1 and Nod2 the thymus, in part based on the requirement for autophagy interact with Atg16L1 (36, 37), of significance for Crohn’s to physiologically reduce the mitochondrial and ER content disease (CD) because Nod2 and Atg16L1 are risk loci for CD in maturing T cells (51–53). (38). NLRC4 (Ipaf) and NLRP4 inhibit autophagy (39) and are found in macromolecular complexes with Beclin 1. RLRs Autophagy in chronic inflammatory and autoimmune diseases activate autophagy with biologically important effects (40), Genetic links between autophagy and chronic inflammatory but thus far, more attention has been given to negative reg- disorders and autoimmune diseases continue to be uncovered ulation of RLR signaling by autophagy factors Atg5–Atg12 by genome-wide association studies (GWAS). Genetic varia- (41) and Atg9 (42). Atg9 negatively regulates trafficking and tions in the PRDM1–ATG5 intergenic region have been as- activation of TBK-1 in the type I IFN response to dsDNA sociated with rheumatoid arthritis (54). Autophagy specifi- (42). cally favors presentation of citrullinated proteins, which may contribute to autoimmune disorders such as rheumatoid ar- Autophagy and inflammasomes thritis (55). The initial GWAS linking of ATG16L1 and Autophagy and inflammasomes interact in two ways (Fig. 1, IRGM [immunity-related GTPase M; a modulator of auto- panel 3). All reports thus far (5, 43–46) agree on the obser- phagy (56, 57)] with CD (38) has been replicated in nearly 50 vation that autophagy plays a negative role in inflammasome independent population studies. Polymorphisms in another activation. Autophagy lowers the basal level of inflammasome autophagy gene, ULK1, are also associated with CD (58). activation by continually removing endogenous irritants (43, Genetic associations of CD with IRGM have been extended 44). For example, autophagy prevents spurious inflammasome to IRGM copy number variants in human populations (59). activation by eliminating defunct mitochondria that otherwise IRGM has further been linked to systemic lupus eryth- represent endogenous sources of inflammasome agonists, such ematosus in a recent meta-analysis of autoimmune diseases as reactive oxygen species (ROS) and mitochondrial DNA (60). GWAS in different populations link ATG5 variants to (43, 44) (Fig. 1, panel 3). In the absence of basal autophagy, systemic lupus erythematosus (61, 62). This genetic evidence endogenous factors lead to inflammasome activation and in- and other studies implicate autophagy in chronic inflamma- creased IL-1b processing and represent sources of sterile in- tory diseases and autoimmune disorders. flammation. This explains how loss of Atg16L1 elevates IL-1b levels in a murine model of CD (47). Conclusions On the flip side, autophagy plays a positive (but only acute, The initial sporadic observations that autophagy can play a role short-term) role in delivering outside the cell the effector in cell-autonomous defense against intracellular bacteria such products of inflammasome activation, such as IL-1b and as Mycobacterium (63) and streptococci (64) have potentially other alarmins, in a process referred to as the been extended in the past several years to various facets of unconventional secretion of IL-1b (5). Although IL-1b and

by guest on October 1, 2021. Copyright 2012 Pageant Media Ltd. immunity. The connections of autophagy with the normal IL-18 do not have signal peptides to deliver them into the function of innate and adaptive immunity at almost every lumen of the organelles of the conventional secretory pathway level, the genetic and functional associations with immuno- (ER–Golgi–plasma membrane), they are released extracellu- logical disorders, and the unique, specialized mechanisms of larly upon inflammasome activation. This is, at least in part, autophagy as stand-alone immune processes presented in this supported by the topological inversion properties of auto- article and elsewhere (2) are consistent with the thesis of this phagy, ferrying molecules from the cytosolic side into the review that autophagy represents a new and growing immu- lumen of putative secretory vesicles. However, this effect nological paradigm. wanes quickly with time, and the downregulation of inflam- http://classic.jimmunol.org masomes by autophagy becomes dominant once again (46). Acknowledgments Thus, autophagy negatively controls inflammasome activation I apologize to colleagues for omissions imposed by space limitations, including (5, 43–46) and positively controls IL-1b secretion per se (5). microbial defenses against autophagy, nonautophagic functions of the ATG The topological inversion action and the positive role of factors, and roles of autophagy processes other than macroautophagy. I thank autophagy in secretion of alarmins are not limited to IL-1b Carolyn Mold for comments on the text and Dara Elerath for graphic design. and extend to HMGB1 (5). Downloaded from Disclosures Autophagy in Ag presentation and T cell homeostasis The author has no financial conflicts of interest. The role of autophagy as a topological inverter (transport from cytosol to lumen) and its other functions contribute to MHC References II presentation of endogenous cytosolic Ags (33, 48, 49) (Fig. 1. Mizushima, N., T. Yoshimori, and Y. Ohsumi. 2011. The role of Atg proteins in autophagosome formation. Annu. Rev. Cell Dev. Biol. 27: 107–132. 1, panel 4). The physiological role of this is manifested in 2. Levine, B., N. Mizushima, and H. W. Virgin. 2011. Autophagy in immunity and immune surveillance of viral (48) and inhibition of inflammation. Nature 469: 323–335. this process by HIV-1 (49). Autophagy-dependent presenta- 3. Manjithaya, R., C. Anjard, W. F. Loomis, and S. Subramani. 2010. Unconven- tional secretion of Pichia pastoris Acb1 is dependent on GRASP protein, peroxi- tion of endogenous Ags plays a part in positive and negative somal functions, and autophagosome formation. J. Cell Biol. 188: 537–546. selection of naive T cell repertoires in the thymus (50). It has 4. Michaud, M., I. Martins, A. Q. Sukkurwala, S. Adjemian, Y. Ma, P. Pellegatti, S. Shen, O. Kepp, M. Scoazec, G. Mignot, et al. 2011. Autophagy-dependent been hypothesized that peripheral tissue autophagic activities anticancer immune responses induced by chemotherapeutic agents in mice. Sci- may have to be matched by central tolerance mechanisms ence 334: 1573–1577. 5. Dupont, N., S. Jiang, M. Pilli, W. Ornatowski, D. Bhattacharya, and V. Deretic. dependent on autophagy in the thymus to prevent autoim- 2011. Autophagy-based unconventional secretory pathway for extracellular delivery munity (50). Autophagy functions in mature T cell homeo- of IL-1b. EMBO J. 30: 4701–4711. The Journal of Immunology 19

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