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An Emerging Immunological Paradigm Vojo Deretic This Information Is Current As J Immunol 2012; 189:15-20; ; of September 24, 2021 Autophagy: An Emerging Immunological Paradigm Vojo Deretic This information is current as J Immunol 2012; 189:15-20; ; of September 24, 2021. doi: 10.4049/jimmunol.1102108 http://www.jimmunol.org/content/189/1/15 Downloaded from References This article cites 64 articles, 25 of which you can access for free at: http://www.jimmunol.org/content/189/1/15.full#ref-list-1 Why The JI? Submit online. http://www.jimmunol.org/ • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average by guest on September 24, 2021 Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2012 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Autophagy: 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- Downloaded from 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]), http://www.jimmunol.org/ 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 September 24, 2021 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 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 regulation and effector functions of pattern recognition occurs in the cytoplasm under the control of signaling systems Department of Molecular Genetics and Microbiology, 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 Downloaded from http://www.jimmunol.org/ by guest on September 24, 2021 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 galectins 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 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,
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