Autophagy and Its Role in MHC-Mediated Antigen Presentation Victoria L. Crotzer and Janice S. Blum This information is current as J Immunol 2009; 182:3335-3341; ; of October 2, 2021. doi: 10.4049/jimmunol.0803458 http://www.jimmunol.org/content/182/6/3335 References This article cites 75 articles, 23 of which you can access for free at: Downloaded from http://www.jimmunol.org/content/182/6/3335.full#ref-list-1 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision http://www.jimmunol.org/ • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: by guest on October 2, 2021 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 © 2009 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Autophagy and Its Role in MHC-Mediated Antigen Presentation1 Victoria L. Crotzer and Janice S. Blum2 Intracellular degradation by autophagy plays a role in hydrolase sorting in yeast (6). Another pathway, xenophagy, in- the maintenance of cellular homeostasis under normal volves the use of the autophagic machinery for the degradation conditions and during periods of cellular stress. Auto- of intracellular pathogens (7). Macroautophagy and CMA have phagy has also been implicated in several other cellular been implicated in the presentation of Ag by MHC molecules processes including immune recognition and respon- and, thus, are the major focus of this review. siveness. More specifically, autophagy has been identi- Macroautophagy is also a constitutively active cellular process modulating the degradation of long-lived proteins and or- fied as a route by which cytoplasmic and nuclear Ag are Downloaded from ganelles (1). During short periods of nutrient deprivation, this delivered to MHC class II molecules for presentation to ؉ pathway is rapidly induced as a mechanism to salvage amino CD4 T cells. Autophagy has also recently been impli- acids. The absence of growth factors or amino acids prevents cated in MHC class I cross-presentation of tumor Ag -؉ signaling through PI3K from activating the autophagy regula and the activation of CD8 T cells. This review dis- tory molecule known as mammalian target of rapamycin cusses the role of autophagy in modulating MHC class (mTOR), and thus, macroautophagy is induced (8). In macro- I and class II Ag presentation as well as its implication autophagy, portions of the cytoplasm are sequestered into dou- http://www.jimmunol.org/ in regulating autoimmunity and tolerance, tumor ble-membrane structures known as autophagosomes. The immunity, and host defense against intracellular formation of the autophagosome requires a number of autoph- pathogens. The Journal of Immunology, 2009, 182: agy-related gene (Atg) products that have been well-character- 3335–3341. ized in yeast (6) and are conserved in mammals; the specific details of autophagosome formation have been reviewed exten- sively elsewhere (2, 8). Briefly, the Atg12-Atg5-Atg16 complex, utophagy is one mechanism that cells use to degrade in conjunction with Atg9, mediates the induction of autopha- cytoplasmic proteins and organelles during the main- gosome formation. During this process, LC3 (Atg8) is conju- by guest on October 2, 2021 A tenance of cellular homeostasis (1). There are multi- gated to phosphatidylethanolamine with the assistance of the ple pathways of autophagy. In microautophagy, small portions Atg4, Atg7, and Atg3 molecules and incorporated into the au- of the cytosol are internalized via lysosomal membrane invagi- tophagosomal membrane. This membrane next expands and nations, and proteins are continuously degraded in the lumen engulfs portions of the cytosol, including entire organelles. of this organelle even under resting conditions (2). Microauto- Upon formation of the autophagosome, the Atg12-Atg5-Atg16 phagy is up-regulated under conditions of cellular stress such as complex dissociates from this structure while LC3 (Atg8)-phos- nutrient deprivation, but studies of this pathway have been lim- phatidylethanolamine remains in the autophagic lumen as an ited to yeast and cell-free systems (3, 4). In mammalian cells, autophagosomal marker. The outer membrane of the autopha- constitutively active autophagy pathways can also be up-regu- gosome fuses with the lysosomal membrane, forming an autoly- lated as a mechanism to salvage amino acids during periods of sosome within which the single membrane structure, or auto- cellular stress. Several types of selective autophagy have been phagic body, is degraded by lysosomal esterases, lipases, and identified in mammalian cells including macroautophagy and proteases. chaperone-mediated autophagy (CMA)3 (Fig. 1), as well as During periods of prolonged cellular stress, bulk autophagy pexophagy and mitophagy (5). A related constitutive biosyn- declines, and the process of CMA is up-regulated. In CMA, spe- thetic pathway, cytoplasm-to-vacuole targeting, is involved in cific cytosolic proteins displaying homologous pentapeptide Department of Microbiology and Immunology and the Walther Oncology Center, Indi- 3 Abbreviations used in this paper: CMA, chaperone-mediated autophagy; ALIS, ag- ana University School of Medicine and the Walther Cancer Institute, Indianapolis, IN gresome-like induced structures; Atg, autophagy-related gene; cTEC, cortical thymic 46202 epithelial cell; DC, dendritic cell; EBNA, EBV nuclear Ag; ER, endoplasmic reticu- lum; GAD, glutamic acid decarboxylase; hsc70, heat shock cognate 70-kDa protein; Ii, Received for publication December 19, 2008. Accepted for publication January 21, 2009. invariant chain; LAMP, lysosome-associated membrane protein; 3-MA, 3-methylad- The costs of publication of this article were defrayed in part by the payment of page charges. enine; MP1, influenza matrix protein 1; mTOR, mammalian target of rapamycin; This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. siRNA, small interfering RNA. Section 1734 solely to indicate this fact. Copyright © 2009 by The American Association of Immunologists, Inc. 0022-1767/09/$2.00 1 V.L.C. is supported by a Career Development Award from the Melanoma Research Foundation. National Institutes of Health AI49589 supported the effort of J.S.B. 2 Address correspondence and reprint requests to Dr. Janice S. Blum, Medical Science Building Room 420, 635 Barnhill Drive, Indianapolis, Indiana, 46202-5120. E-mail ad- dress: [email protected] www.jimmunol.org/cgi/doi/10.4049/jimmunol.0803458 3336 BRIEF REVIEWS: AUTOPHAGY AND ANTIGEN PRESENTATION class I presentation pathway is still under investigation, al- though several routes have recently been proposed. These path- ways have been described extensively elsewhere (11–13); thus, only a brief summary of the current models of class I-mediated cross-presentation is offered here. Studies have suggested that MHC class I molecules may ac- quire peptides derived from exogenous Ag internalized into phagosomes in a TAP-dependent or TAP-independent man- ner. In the TAP-dependent phagosome-to-cytosol-to-phago- some pathway, Ag is transported to the cytosol by a yet un- known mechanism, possibly Sec61, and degraded by the proteasome. Peptides are then reimported into the phagosome, FIGURE 1. Pathways of autophagy in MHC class II-mediated Ag presen- which has acquired TAP as well as other ER proteins such as tation. In macroautophagy, the cytoplasm is sequestered into double-mem- MHC class I. The phagosome-to-cytosol pathway calls for pep- brane structures known as autophagosomes, which fuse with lysosomes. In tides generated in the cytosol by the proteasome to be directly CMA, specific cytosolic proteins are transported into lysosomes via a molecular transported to MHC class I molecules in the ER via TAP. An- chaperone/receptor complex composed of hsc70 and LAMP-2A. other possible mechanism of class I-restricted cross-presenta- tion may involve the ER-associated degradation pathway. Here, exogenous Ag internalized in endosomes is transported into the Downloaded from motifs bind to a molecular chaperone complex composed of ER, translocated for degradation in the cytosol by the protea- multiple heat shock proteins including the heat shock cognate some, and finally transported back into the ER by TAP. It has 70-kDa protein (hsc70) (reviewed in Ref. 9). This molecular also been reported that DC may acquire exogenous peptides ϩ chaperone complex transports the substrate protein to the lyso- from other cells via gap junctions to cross-prime naive CD8 T somal membrane, where it associates with an isoform of the ly- cells. Lastly, in the vacuolar pathway, MHC class I molecules http://www.jimmunol.org/ sosome-associated membrane protein (LAMP) 2A, which func- may acquire peptides that are generated in phagosomes by cys- tions as part of the lysosomal receptor for CMA. The teine proteases such as cathepsin S in a TAP-independent man- cytoplasmic domain of LAMP-2A serves as a potential docking ner. The mechanisms that potentiate MHC class I peptide load-