The Journal of Immunology, 2006, 177: 4945-4951.
Copyright © 2006 by The American Association of Immunologists, Inc.
Autophagy: Eating for Good Health1
Michele S. Swanson2
Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI 48109
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Abstract
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A renaissance in the autophagy field has illuminated many areas of biology, and infectious disease is no exception. By identifying key components of this broadly conserved membrane traffic pathway, yeast geneticists generated tools for microbiologists and immunologists to explore whether autophagy contributes to host defenses. As a result, autophagy is now recognized to be another barrier confronted by microbes that invade eukaryotic cells. Mounting evidence also indicates that autophagy equips cells to deliver cytosolic Ags to the MHC class II pathway. By applying knowledge of the autophagy machinery and exploiting microbes as genetic probes, experimentalists can now examine in detail how this ancient membrane traffic pathway contributes to these and other mechanisms critical for infection and immunity.
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Introduction
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Autophagy enables eukaryotic cells to capture cytoplasmic components for degradation within lysosomes. Classically studied as a response to nutrient stress, this catabolic mechanism contributes to many physiological and pathological processes, including morphogenesis, cancer, neurodegenerative disorders, and infectious diseases (1, 2, 3, 4). A morphological feature unique to autophagy is the sequestration of cytoplasmic material within double-membraned cisternae, which then fuse to form isolation vacuoles (Fig. 1). Consequently, proteins and organelles that once were endogenous enter the pool of exogenous matter, without crossing a membrane barrier. The isolation membrane of mammalian autophagosomes is thought to originate either from the endoplasmic reticulum (ER),3 a post-Golgi compartment, or a novel organelle called the phagophore (5). Genetic studies in yeast established that lipid flow from the ER through the early secretory pathway is required for autophagosomes to form (6). As autophagosomes mature, they acquire lysosomal components, and their cargo is degraded (7).
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FIGURE 1. Morphological hallmarks of autophagosome biogenesis. Through the action of the Atg7 enzyme, membranes derived from the secretory pathway form an isolation membrane that sequesters organelles and other cytosolic components. Atg7 conjugates Atg12 to Atg5, then Atg8 (LC3) to phosphatidylethanolamine in the isolation membrane. Atg8 (LC3), a second conjugating enzyme, remains associated with the autophagosomal membrane and promotes its maturation into an autophagolysosome. Autophagy is stimulated by a class III PI3K that is inhibited by wortmannin and 3MA. An endogenous inhibitor of autophagy is the TOR; rapamycin relieves inhibition by TOR. Monodansyl-cadaverine (MDC) is a fluorescent reagent that accumulates in acidic autophagolysosomes, organelles that also acquire late endosomal and lysosomal components such as LAMP1 and 2 and cathepsin D. For a more complete description of autophagosome biogenesis, see Refs. 5 6 7 8 9 10 11 12 13 14 15 16 . That autophagy represents a point of convergence for the secretory and the endosomal pathways suggests a number of interesting implications for immunity.
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In organisms as diverse as plants and humans, autophagosome biogenesis is controlled by a regulated protein conjugation system, which in yeast is composed of more than two dozen proteins designated Atg (8, 9). When autophagy is stimulated, the cytosolic ubiquitin E1-like activating enzyme Atg7 redistributes to the isolation membrane. There, it first catalyzes the conjugation of Atg12 to Atg5, then of Atg8 (MAP1LC3, GATE-16, and GABARAP in mammals) directly to phosphatidylethanolamine, thereby promoting the formation and expansion of the nascent autophagosome. As the most stable and specific of the known autophagy components, the ubiquitin E1-like activating enzyme Atg8/LC3 is currently the field’s gold standard diagnostic tool (10, 11, 12). Since mammalian cells require a class III PI3K to generate autophagosomes, wortmannin or 3-methyladenine (3MA) inhibits the pathway (13). A negative regulator of autophagy is the Target of Rapamycin protein (TOR) kinase; its inhibition is relieved by rapamycin (14), another valuable tool for experimentalists. Recent reviews provide a more comprehensive introduction to autophagy and reagents that affect the process (2, 7).
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Out of the frying pan, into the fire
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The autophagy pathway engulfs and degrades a variety of bacteria that invade the cytoplasm (Table I), establishing its credentials as a component of innate immunity. For example, to escape delivery to deathly lysosomes, some pathogens puncture their phagosomal membranes. However, once liberated, the cytosolic bacteria become targets of autophagy. Such is the fate of Group A Streptococcus, antibiotic-treated Listeria monocytogenes, Salmonella enterica, and Francisella tularensis that become free in the cytoplasm (15, 16, 17, 94). Although the mechanism remains to be determined, it appears that autophagy is activated by a host surveillance system that monitors the cytosol, not the phagosomal lumen, since mutant bacteria that fail to escape their vacuoles do not activate the autophagy machinery (15, 16, 17, 94).
A variety of virulent bacteria that persist within specialized replication vacuoles in mammalian cells also encounter the autophagy pathway (Table I). However, such pathogens typically deliver virulence factors into the cytoplasm using secretion systems that breach the phagosomal membrane. While depositing their payload, intracellular pathogens likely leave calling cards for the innate immune system. For example, Legionella pneumophila, Brucella abortus, and perhaps Coxiella burnetii each need type IV secretion for sustained interactions with the ER and autophagic proteins (18, 19, 20, 21). However, during type IV secretion, peptidoglycan of Helicobacter pylori and flagellin of L. pneumophila apparently leak into the cytoplasm (22, 23). Likewise, when the S. enterica type III secretion system is active, flagellin is predicted to taint the cytoplasm (24); concomitantly, autophagy is induced (17, 25). Both flagellin and peptidoglycan are pathogen-associated molecular patterns that are detected by nucleotide oligomerization domain-like receptors (NLRs), components of the cytosolic surveillance machinery of the innate immune system (23, 26, 27). Thus, host cells may elevate autophagy as a barrier to pathogens that either invade the cytosol or deposit in the cytoplasm a virulence payload that is tainted with pathogen-associated molecular patterns, a model discussed in more detail below.
Alternatively, it is conceivable that certain intracellular pathogens deliver to the host cytosol virulence factors to recruit the autophagy machinery. Ectopic expression by transfected COS-2 cells of the S. enterica SipB protein induces autophagosome formation (25), and bacterial protein synthesis is a prerequisite for autophagosome formation during infection by C. burnetii or S. enterica (17, 28). However, what advantage entry into the autophagolysosome pathway might confer to microbes is not clear. Indeed, to steer clear of toxic lysosomes, such intrepid pathogens presumably require additional factors either to inhibit autophagosome maturation or to masquerade their vacuoles as ageless autophagosomes. For comprehensive descriptions of the encounters between particular microbes and the autophagy pathway, see the recent series of reviews in Autophagy (
www.landesbioscience.com/journals/autophagy
).
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Microbes strike back
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Mammalian cells may enlist autophagy not only to degrade abnormal endogenous proteins that pollute the biosynthetic pathway, but also to confront certain viruses. In some people, 
1-antitrypsin deficiency manifests as liver disease: as mutant forms of this protease inhibitor build up, their hepatocytes accumulate autophagic vacuoles, a histopathology that is exacerbated by inhibitors of autophagy (29). Molecular genetic analysis of 1-antitrypsin deficiency in both yeast and mice confirmed that protein aggregates that accumulate on ER membranes induce autophagy (30, 31). Autophagy is also critical for normal neuronal cells to eliminate the basal level of protein aggregates that accumulate in the cytoplasm: when autophagy is inhibited genetically, neurodegeneration ensues (32, 33).
Poliovirus, mouse hepatitis virus, severe acute respiratory syndrome coronavirus, and the equine arterivirus are positive-strand RNA viruses that assemble their replication complexes on the ER; each also triggers formation of autophagosome-like vacuoles (34, 35, 36). In the case of poliovirus and equine arteritis virus, ectopic expression of just two viral proteins is sufficient to activate the host autophagy pathway, as judged by the accumulation of double-membraned vesicles that contain Atg8/LC3 (34, 37). Nevertheless, some positive-stranded RNA viruses exploit components of the autophagy machinery to produce new virions, since the yield of extracellular virus declines when autophagy is perturbed genetically or pharmacologically (35, 36). Therefore, this class of viruses provides a rich source of reagents for experimentalists to probe the contributions of autophagy to viral infection and immunity.
If mammalian cells routinely elevate autophagy to protect their cytoplasm from infection, pathogens that thrive in the cytosol must counteract this defensive maneuver. Herpes simplex virus and Shigella flexneri do just that. Double-stranded RNA generated by herpes simplex virus induces a conformational change in the host protein, protein kinase R (PKR), triggering phosphorylation of an array of effector proteins. When phosphorylated by PKR, the translation factor eukaryotic initiation factor 2 is inactivated, protein synthesis is inhibited, and autophagy is induced (38). To avoid this onslaught, the virus encodes ICP34.5, a virulence protein that short-circuits the autophagy response by activating an eukaryotic initiation factor 2-specific phosphatase (38, 39). When herpes virus lacks ICP34.5, its virions are degraded within autophagosomes (40). As its weapon, the bacterial pathogen S. flexneri releases the virulence protein IscB by type III secretion (41). By interfering with binding of Atg5 protein to IscA, a key bacterial factor, IscB, is thought to camouflage S. flexneri from the host cytosolic scavenger system. In the absence of IscB, S. flexneri that escape into the cytoplasm are engulfed and degraded within autophagolysosomes (41). As tools to analyze the autophagy machinery are applied more widely, we can expect discovery of more strategies pathogens implement to evade, inhibit, or tolerate autophagy.
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An exclusive escort service delivers cytoplasmic proteins to the MHC class II (MHCII) pathway
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Besides degrading microbial intruders, autophagy has been implicated in delivery of cytoplasmic Ags to the MHCII pathway (42). Chaperone-mediated autophagy is a specialized protein degradation pathway of cells. As its name implies, this form of autophagy is conducted by a dedicated machinery comprised of cytoplasmic chaperones, located in both the cytoplasm and the vacuole lumen, and a receptor that spans the endosomal membrane. When amino acids are limiting, polypeptides are transported directly across membranes and into the lumens of late endosomal vacuoles (43). Cargo specificity is a key feature that distinguishes chaperone-mediated autophagy from the bulkvariety, "macroautophagy." To be recognized as a substrate for the receptor-mediated degradation pathway, target proteins must encode a short motif related to the sequence KFERQ, which occurs in 
30% of cellular proteins (43).
Although typical substrates of chaperone-mediated autophagy include a number of metabolic enzymes (43), microbial Ags can also be substrates of chaperone-mediated autophagy. Presentation to CD4+ T cells by EBV-transformed human B cells of peptides derived from two cytoplasmic proteins correlates with the level of expression of two components of chaperone-mediated autophagy, the LAMP2a receptor and the Hsc70 chaperone (42). However, LAMP2 isoforms have also been implicated in macroautophagy, as judged by phenotypic analysis of mice that lack the corresponding gene (44). To assess the relative contributions of chaperone-mediated autophagy and macroautophagy to MHCII presentation of endogenous Ags, inhibitors specific for each degradation pathway are available (45). Given its strict requirement for substrate recognition, chaperone-mediated autophagy appears ill-suited for cytosolic surveillance for microbial Ags.
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Ubiquitin as a marker of substrates of autophagy
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Autophagic degradation of aggregates of ubiquitinated proteins is a broadly conserved cellular mechanism to eliminate malformed proteins (46). Whether ubiquitination itself is sufficient to target soluble proteins for autophagic degradation remains an open question, although a number of interactions between the two pathways have been documented. Free ubiquitin and ubiquitin conjugants are found within autophagosomes (47, 48), predominantly in autophagolysosomes (49). The E1 ubiquitin-conjugating enzyme equips cells to accelerate autophagosomal degradation of proteins in response to heat-stress (50, 51), apparently by promoting proteolysis by autophagolysosomes, rather than their biogenesis (49). Although their proteasomes function normally, mice that lack the autophagy enzyme Atg7 amass aggregates of ubiquitinated proteins within their liver cells (52). Furthermore, when either Atg5 or Atg7 function is disabled in neural cells of mice, polyubiquitinated proteins accumulate and then aggregate. Despite normal proteasome activity, neurodegeneration results, dramatically demonstrating that autophagy is critical for neural cells to prevent protein aggregates from reaching toxic levels (32, 33).
Two proteins that link ubiquitinated aggregates to the autophagy pathway have been described. For clusters of misfolded proteins to associate with the autophagy enzyme LC3 (Atg8), they must first be decorated by p62, a protein that binds polyubiquitin directly (53). Bundles of ubiquinated cytosolic proteins may also be directed to the autophagy pathway by Alfy, the autophagy-linked FYVE-domain-containing protein (54). In response to nutrient stress, this broadly conserved and expressed protein translocates from the nuclear membrane to occupy filamentous structures woven among aggregates of ubiquitin conjugants. Some of the Alfy-decorated protein complexes can be found within vacuoles that contain Atg5 and LC3 (Atg8). It is tempting to speculate that binding of its FYVE domain to the signaling lipid phosphatidylinositiol-3-phosphate may equip Alfy to nucleate autophagosome formation at the site of cytosolic protein aggregates (54).
Whether professional APCs rely on autophagy to shape the profile of Ags routed for presentation is another topic of active pursuit (55). When treated with LPS or infected by influenza virus, dendritic cells and macrophages recruit, ubiquitinate, and store cytosolic proteins within dynamic assemblies known as aggresome-like induced structures (ALISs) (56, 57, 58). Dendritic cells rapidly store newly formed proteins (56), a pool that in infected cells includes viral Ag (58). Deposition of proteins in ALIS occurs as dendritic cells mature, migrate to the thymus, and synthesize costimulatory molecules and cytokines. If ALISs are degraded preferentially by APCs within lymph nodes, their expression of critical costimulatory molecules and inflammatory cytokines would coincide with their display of microbial Ags to T cells (55, 58). Such orchestrated formation and processing of ALISs is predicted to favor tolerance of self-Ags and to promote a specific immune response to the infectious agent (55, 57).
Direct evidence for delivery of Ags from ALIS to either the MHC class I (MHCI) or MHCII pathway is lacking, but a number of observations are consistent with such a role. Dendritic cells are thought to enlist proteasomes to degrade these protein aggregates because ALISs accumulate when proteasome activity is inhibited pharmacologically (56). However, macrophages and other cells rely on autophagy to process ALISs because these structures accumulate when autophagy is blocked genetically or chemically (59). Therefore, it is of interest to investigate whether APCs exploit ALISs as a reservoir of cytosolic proteins destined either for the MHCI pathway after rapid processing by proteasomes or for the MHCII pathway after more gradual degradation within autophagolysosomes.
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Indiscriminate delivery of cytosolic proteins to the MHCII pathway
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As a bulk mechanism to engulf cytosolic components for subsequent lysosomal degradation, autophagy has the capacity to deliver a broad spectrum of endogenous Ags to the MHCII pathway (60, 61, 62, 63, 64). For example, after starvation for 6 h, the autophagosomal compartment of human B lymphoblastoid cells doubles in size, and the frequency of cytosolic peptides bound to MHCII increases markedly, whereas presentation of exogenous Ags does not (64). When autophagy is inhibited, presentation of cytosolic Ags by MHCII declines, but the MHCI pathway is not affected (61, 62, 63). In EBV-transformed cells, the nuclear Ag 1 (EBNA1) not only traffics through autophagosomal vacuoles, but also stimulates CD4+ T cells by a mechanism independent of proteasome function (62). However, when autophagy is inhibited, either by 3MA or small interfering RNAs specific for the Atg12 protein, presentation of EBNA1 by the MHCII pathway to CD4+ T cell is markedly reduced. The observation that autophagy can deliver cytoplasmic Ags to the MHCII pathway to activate CD4+ T cells raises the question, are cells equipped to induce autophagy in response to infection?
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IFN- induces autophagy
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When activated by IFN-, cells acquire the capacity to capture and degrade at least two different intracellular pathogens. The Rickettsiae escape from phagosomes to replicate in the cytosol of host cells. However, when treated with TNF- and IFN-, mouse endothelial cells engulf and digest cytosolic Rickettsia conorii within autophagosomal vacuoles (65). Likewise, activation of macrophages with IFN- induces autophagy of the vacuolar pathogen, Mycobacterium tuberculosis (66). Once macrophages are activated, nearly twice as many bacteria are found within autophagosomal vacuoles, as judged by their acidic pH, lysosomal proteins LAMP-1, cathepsin D, and proton ATPase, and the autophagy proteins Atg6 and Atg8, and the number of viable M. tuberculosis within activated macrophages declines by half (66). Its intimate association with cholesterol-rich membranes somehow enables M. tuberculosis to evade recognition or clearance by the autophagy machinery (67). In HeLa cells, induction of autophagy by either IFN- or amino acid starvation is promoted by two calmodulin-dependent protein kinases, the death-associated protein kinase and the DAPk-related kinase 1 (68). Delineating the circuitry that equips cells to activate autophagy in response to cytokine stimulation is an area ripe for investigation.
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The inflammasome, a smoking gun of autophagy battles
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Another potential link between autophagy and innate immunity is suggested by studies of intracellular pathogens that activate the inflammasome. This protein complex, comprised of caspase-1 and a number of adaptor proteins of the NLR family (69), is activated by microbial products in the cytosol. Detection of S. enterica, L. monocytogenes, S. aureus, F. tularenesis, and L. pneumophila is mediated by particular NLR adaptor proteins, as judged by the vulnerability of the corresponding mouse mutants (27, 70, 71, 72, 73).
In response to cytosolic contamination, the inflammasome initiates a proinflammatory cell death. Unlike apoptotic cells, cells undergoing "pyroptosis" rapidly release IL-1
and IL-18 from their permeable plasma membranes, hence the term’s derivation from the Greek pyro, to invoke fire or fever, and ptosis, or "falling," to emphasize a death program that requires caspase-1 (74). It is striking that each of the intracellular pathogens known to trigger pyroptosis also stimulates autophagy (Table I); these include S. flexneri (75, 76), S. enterica (77, 78), F. tularensis (71, 94), and L. pneumophila (23, 27, 73). Moreover, in mouse macrophages, the amount of the NLR protein Naip5 correlates not only with robust proinflammatory death but also with autophagosome maturation (23). Naip5 appears to equip macrophages to detect cytosolic flagellin, directly or indirectly, since Naip5+ macrophages degrade flagellate L. pneumophila by a process that resembles autophagy, whereas flagellin mutants not only replicate freely in Naip5+ mouse macrophages, but also avoid rapid clearance within mouse lungs (23). Accordingly, it will be worthwhile to test directly whether inflammasomes provide a mechanism for macrophages to respond to cytosolic microbial contaminants not only by releasing inflammatory cytokines and committing suicide, but also by degrading bacteria by autophagy.
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Outlook
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Only recently have microbiologists and immunologists come to appreciate the myriad contributions of autophagy to infection and immunity. Since the autophagy machinery synchronizes an intersection between secretory and endosomal traffic, it is also worth testing whether this ancient membrane traffic pathway orchestrates a number of heretofore unexplained cellular processes of the immune system. For example, TLR9 responds to its ligand by translocating from the ER to endosomal vacuoles and then to lysosomes (79, 80), a route expected for a component of autophagosomes. Second, although the ER is not a major contributor to phagosome biogenesis (81), a population of phagosomes that contain components of the ER and that are competent to mediate proteasome- and TAP-dependent presentation of endogenous Ags on MHCI (82, 83, 84, 85) could be generated by the autophagy machinery. Finally, Unc93b1 is a newly described, although highly conserved, protein of mice that resides on the ER (86); perhaps a role in autophagy accounts for its ability to promote TLR9 signaling, processing, or presentation of exogenous Ags on MHCI, and resistance to mouse herpesvirus and S. aureus. Armed with microbes as genetic probes and the wealth of knowledge and tools generated by autophagy specialists, experimentalists are now in an excellent position to ascertain how this ancient membrane traffic pathway contributes to microbial digestion, Ag presentation, and immune cell signaling.
Note added in proof.
Recently, CD40-activated macrophages have been shown to eliminate the eukaryotic parasite Toxoplasma gondii by autophagy (95), and a critical role for immunity-related GTPases in autophagic clearance of the intracellular pathogens T. gondii and M. tuberculosis by mouse and human macrophages has been demonstrated (96, 97).
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Footnotes
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The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 My laboratory’s studies of the fate of L. pneumophila in macrophages are supported by National Institute of Allergy and Infectious Diseases of the National Institutes of Health Grant R01 AI040694-06AI. 
2 Address correspondence and reprint requests to Dr. Michele S. Swanson, Department of Microbiology and Immunology, University of Michigan Medical School, 6734 Medical Sciences Building II, 1150 West Medical Center Drive, Ann Arbor, MI 48109-0620. E-mail address: mswanson{at}umich.edu
3 Abbreviations used in this paper: ER, endoplasmic reticulum; 3MA, 3-methyladenine; TOR, Target of Rapamycin protein; NLR, nucleotide oligomerization domain-like receptor; PKR, protein kinase R; MHCII, MHC class II; Alfy, autophagy-linked FYVE-domain containing protein; ALIS, aggresome-like induced structure; MHCI, MHC class I.
Received for publication April 27, 2006.
Accepted for publication July 14, 2006.
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Abstract
Introduction
