International Immunology Advance Access originally published online on September 7, 2009
International Immunology 2009 21(11):1199-1204; doi:10.1093/intimm/dxp088
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review-article |
Molecular basis of canonical and bactericidal autophagy
Department of Cellular Regulation, Division of Cellular and Molecular Biology, Research Institute for Microbial Diseases, Osaka University, Yamadaoka 3-1, Suita, Osaka 565-0871, Japan
Correspondence to: T. Yoshimori; E-mail: tamyoshi{at}biken.osaka-u.ac.jp
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Abstract |
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Top
Abstract
IntroductionAutophagy is a catabolic process by which cells degrade their own cytoplasmic constituents. Cells respond to the stress response of nutrient deficiency by degrading a portion of their cellular components to produce amino acids and energy. Recently, it became evident that the autophagic machinery is also involved in a kind of innate immune system. Some bacteria that invade mammalian cells are eventually entrapped in an autophagic membrane structure. In this review, we describe the current understanding of three of the basic components of the canonical autophagy machinery—LC3, the Atg16L complex and phosphatidylinositol 3-phosphate (PI3P)—which are dynamically associated with the autophagic structure. LC3 is proposed to function in autophagosome closure, whereas the Atg16L complex functions as an E3-like protein in ubiquitination-like reactions in the LC3 lipidation system. PI3P is a key determinant of the autophagic membrane. Further, their relation to bactericidal autophagy (i.e. xenophagy) will be introduced.
Keywords: Atg14, Atg16L, LC3, PI3P, xenophagy
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Introduction |
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Autophagy is a universally conserved eukaryotic cellular process by which cells degrade their own cytoplasmic constituents (1). It is best understood as a stress response to nutrient deficiency, when cells degrade a portion of themselves to supply amino acids and energy, and it is induced through the signaling pathway involving the Tor (target of rapamycin) protein kinase (2). It must be conducted in a well-ordered manner, otherwise disordered degradation can threaten cell viability (3). To assure the safety of the autophagic process, it is critically important that the maintenance and disruption of membrane barrier are tightly regulated. Specifically, degradation substrates are segregated within the inner membrane of a double lipid bilayer membrane-bound spherical structure with a diameter of 500–1000 nm, called an autophagosome (Fig. 1). The formed autophagosome moves toward the center of the cell, where the lysosomes are accumulated, along dynein-motored microtubules (4). The outer membrane of the autophagosome fuses with the lysosomal membrane and then the lysosomal hydrolases, proteases and lipases disrupt the inner autophagosome membrane and eventually degrade the contents. Upon the induction of autophagy, hundreds of autophagosomes are generated, resulting in the degradation of a portion of cytoplasmic materials, while the remainder is preserved intact.
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The molecules involved in the formation of the autophagosome are collectively called Atg (autophagy-related proteins; Table 1). Originally identified in yeast, Atg are highly conserved among eukaryotes (5). Recently, in addition to their role in canonical autophagy, Atg involvement in other cellular processes has become evident. For example, they are associated with the sequestration of invading bacteria in mammalian cells (6). The process is called xenophagy and is now regarded as a kind of novel innate immune response. In this review, we will describe what is known about a few representative Atg proteins and their association with xenophagy.
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LC3 in autophagosome membrane formation |
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For a long period of time, visualization of the autophagosome was only possible by electron microscopy, but fluorescent microscopy has made it possible to use LC3 (microtubule-associated protein 1 light chain 3) to label the autophagosome (7). There are at least three mammalian LC3 proteins (LC3A, LC3B and LC3C), which have significant homology to yeast Atg8 (8). There are also at least three other Atg8 paralogues in mammals: GABARAP (
-aminobutyric acid A receptor-associated protein); GABARAPL1 (GABARAP-like 1)/Atg8L (Atg8-like)/GEC1 (glandular epithelial cell 1); and GATE-16 (Golgi-asociated ATPase enhancer of 16 kDa)/GEF2 (ganglioside expression factor2)/GABARAPL2. Although these proteins localize to the autophagosome membrane, details regarding functional difference remain incompletely defined (9, 10). Immediately after being translated from messenger RNA, most of the C-terminal portion of the LC3 protein is cleaved off by Atg4 proteases, and the glycine residue becomes the new C-terminus (11). This form is termed LC3-I and is a soluble protein (7). Another form of LC3 behaves as an integral membrane protein because it is anchored to the lipid in the membrane (7). At the carboxyl base of the C-terminal glycine of LC3-I, an amine base in the head group of phosphatidylethanolamine (PE) binds via an amide bond, and this form is termed LC3-II (12). LC3-II localizes exclusively on the autophagosome. Therefore, a green fluorescent protein (GFP)–LC3 fusion protein has been used to demonstrate autophagosome formation, based on punctuate staining in nutrient-deficient cells (7). LC3 is then removed off from PE by the action of Atg4 proteases (11). LC3 trapped in the autophagosome is degraded after the lysosome fuses with the autophagosome (13). Therefore, the autolysosome, a hybrid structure of the autophagosome and lysosome, lacks intact LC3.
Recently, the function of LC3 in autophagosome formation has been proposed. Ablations of LC3-II, by two independent methods, resulted in the accumulation of unclosed autophagosomes (14, 15). Interestingly, yeast Atg8–PE has the capacity to induce hemifusion in Atg8–PE-associated vesicles in vitro (16). On the basis of these reports, we have proposed a novel model, the reverse fusion model, in a recently published review in which LC3 directly catalyzes the autophagosome closure process (17). We called the model reverse fusion because the membrane dynamics of autophagosome closure proceeds in a reversed order of typical membrane fusion event that is influenza virus escape from the endosome into the cytosol of the host cell.
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LC3 and bacterial sequestration |
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The linkage between autophagy and bacterial invasion became evident in GFP–LC3-expressing mammalian cells, when GFP–LC3 signals surrounded invading Mycobacterium tuberculosis in the phagosome and Group A streptococci (GAS), Salmonella and Shigella in the cytoplasm (18–21). In the case of GAS, which are Gram-positive bacteria, after the bacteria enter HeLa (a mammalian epithelial cell line) via the endocytic pathway, they escape from the endosome to the cytosol through the pore generated by their hemolytic exotoxin, streptolysin O. Eventually they are surrounded by membrane structure called Group A streptococci-containing autophagic vacuole (GcAV).
Although GcAV seems to posses several characters in common with the canonical autophagic structure, including an association with LC3 molecules, there are obvious differences between the two. For example, the size of the GcAV (
10 µm in diameter) is much larger than the canonical autophagosome whose diameter is 1 µm. Recently, we reported that the GcAV is formed through fusion of multiple sac-like precursor structures, which resembles the precursor of the canonical autophagosome (H. Yamaguchi, I. Nakagawa, A. Yamamoto, A. Amano, T. Noda and T. Yoshimori, submitted for publication). The identity of this precursor is still unknown and it is possible that this is the isolation membrane in canonical autophagy.
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The Atg16L complex in autophagosome formation |
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Ubiquitin labels eukaryotic proteins and thereby controls their stability, function, localization and degradation. Ubiquitination of proteins is sequentially undertaken by various enzymes in the E1–E2–E3 cascade (ubiquitin activation–conjugation–ligation). Several other eukaryotic systems operate in a similar way and LC3 belongs to such a ubiquitin-like protein family (22). It is activated by E1 (Atg7) and E2 (Atg3) enzymes just like the ubiquitination reaction (12). The three-dimensional structure of the LC3 family proteins forms a ubiquitin fold and two additional alpha-helical stretches at the N-terminus (23). Interestingly, in the autophagy machinery, another ubiquitin-like molecule, Atg12, is also involved (24). In contrast to LC3, which is conjugated to and deconjugated from PE in a reversible manner, once Atg12 is conjugated to its target molecule, Atg5, it remains conjugated. The three-dimensional structure of Atg5 consists of two ubiquitin folds and Atg12, which also forms a ubiquitin fold, is conjugated to the region between them (25, 26). Therefore, Atg12–Atg5 conjugates form three ubiquitin folds, though biological significance of this interesting feature is still to be determined.
Atg12–Atg5 does not exist as monomer but as multimer in a cell. Atg5 binds to Atg16 (Atg16L in mammals) and Atg16 itself forms a multimer. Therefore, multiple Atg12–Atg5 and Atg16L constitute a super protein complex (27). This complex is mostly soluble in the cytosol but when autophagy is induced, it forms puncta localization, which represents the autophagosome formation (28). It is interesting that once the autophagosome is completely formed, this localization pattern disappears and the protein complex becomes dispersed throughout the cytosol. Further, in contrast to LC3-II, which is localized to both the inner and the outer cytosolic surface of the forming autophagosome, the Atg16L complex localizes exclusively at the outer surface of the forming autophagosome (29).
Recently, the function of the Atg16L complex has been uncovered. It acts as an E3-like enzyme in the LC3 lipidation reaction. This is based on the following observations: (i) Atg3, the E2 enzyme involved in LC3 lipidation, binds to Atg12 and a point mutation that prevents this binding leads to a defect in the lipidation reaction (30). (ii) A defect in the membrane association of the Atg16L complex leads to defects in the lipidation (30). (iii) Forced ectopic localization of the Atg16L complex in the plasma membrane leads to an ectopic lipidation reaction (30). (iv) A yeast Atg12–Atg5 conjugate facilitates the Atg8 lipidation reaction in vitro (31). The localization of the Atg16L complex has only been reported in the forming autophagosome, therefore it is highly possible that the LC3 lipidation reaction occurs at the outer surface of the forming autophagosome. It is considered that the Atg16L complex may deliver LC3 on the forming autophagosome and subsequently LC3 functions in the closing of the autophagosome.
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The Atg16L complex in bacterial sequestration |
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In Atg5-knockout cells, GFP–LC3 failed to surround invaded GAS (19), highlighting the E3 role of Atg16L complex even in the case of GcAV formation. Further, we have observed the association of GFP–Atg5 with the precursor structure of GcAV (Yamaguchi et al., submitted for publication). Another group reported that formin binding protein 1-like (FNBP1L), an F-BAR (Fer/CIP4-homology Bin–Amphiphysin–Rvs)-containing protein, directly binds to Atg3 (which is E2-like) and is specifically involved in Salmonella xenophagy (32). In Atg5-knockout cells, GAS, which enters mouse embryonic cells, can multiply more efficiently than in wild-type cells, establishing the cell-protective role of xenophagy (19). Atg16L-knockout mouse embryo fibroblast (MEF) cells also showed reduced cell-protective ability against invaded Salmonella and Listeria (33). Further, Atg16L1-deficient macrophages produce high amounts of the cytokines IL-1β and IL-18 after stimulation with LPS in a Toll/IL-1R-domain-containing adapter protein-inducing IFN-β (TRIF)-dependent manner (33). Mice lacking Atg16L1 in hematopoietic cells are highly susceptible to colitis (33). Thus, Atg16L1 is important in the control of the endotoxin-induced inflammatory immune response involving inflammasomes.
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The Atg16L complex in Crohn's disease |
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Mammalian Atg16L posses tryptophan–aspartic acid (WD) repeats that are absent in yeast Atg16. WD repeats generally function in recognizing some other protein, as exemplified by the Skp, Cullin, F-box-containing complex E3 protein that is involved in ubiquitination and recognizes its target through the WD repeat. Recent genome-wide single-nucleotide polymorphism (SNP) analysis revealed that a SNP in the Atg16L WD repeat (T300A) is closely linked with susceptibility to Crohn's diseases, a complex inflammatory disease of the small intestine (34, 35). The study using Atg16L1-knockdown and transient expression of Atg16L1 (T300A) reported defective xenophagy against Salmonella (36).
Atg16L1-hypomorphic mice expressing the T300A mutation in the WD domain showed defects in the granule exocytosis pathway of the Paneth cell, a specialized epithelial cell that secretes antimicrobial peptides (37). Further, patients who had Crohn's disease and were homozygous for the Atg16L1 T300A showed similar phenotypes in their Paneth cell granules (37). Therefore, it is still confusing whether autophagy or xenophagy is directly involved in Crohn's diseases (also see the review by Meixlsperger and Münz in this issue).
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Phosphatidylinositol 3-phosphate generation during autophagosome formation |
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Autophagosome formation involves the generation of the cell membrane phospholipid, phosphatidylinositol 3-phosphate (PI3P) (38). This is dependent on autophagy-specific phosphatidylinositol 3-kinase (PI 3-kinase) complexes. In the case of yeast, this complex consists of at least four subunits, namely Vps34 (vacuolar protein sorting 34; a PI 3-kinase), Vps15 (a protein kinase), Vps30/Atg6 and Atg14 (39). Vps34, Vps15 and Atg6 participate in other cellular process too, and Atg14 determines the specificity of this complex.
In the case of mammalian cells, Beclin-1 is the homolog of Atg6, and it binds to hVps34 (human Vps34; a Class III PI 3-kinase) (40), and as such, Beclin-1-knockout mice are defective in autophagy (41). The mammalian paralogue of Atg14 has been elusive for a long time, but recently four independent groups identified mammalian Atg14 (42–45). Although its sequence similarity is not very high, Atg14-knockout MEF cells show complete inhibition of autophagy indicating that it is bona fide mammalian Atg14 counterpart (43). Another protein UV radiation resistance-associated gene (UVRAG) binds to the Atg14-binding site of Beclin-1 in a mutually exclusive manner. UVRAG complex is postulated to function in the endosome–lysosome and autophagosome–lysosome fusion processes (46).
Another protein, Rubicon, binds to the UVRAG complex and negatively regulates the endosome–lysosome and autophagosome–lysosome fusion processes (43, 45). Interestingly, knock down of Rubicon leads to the induction of autophagy even under nutrient-rich conditions, implying the existence of some feedback mechanism from lysosomal fusion to autophagosome formation (43). These studies indicated that Beclin-1 plays a role in multiple cellular processes, in addition to autophagy.
GFP–Atg14L was localized to the endoplasmic reticulum (ER), although it was shown only when over-expressed. When autophagy is induced under starvation, GFP–Atg14L forms dot-like structures that co-localize with Atg16L (43).
Recently, a very interesting report prompted us to investigate whether the ER localization of the Atg14L complex may have functional significance. Double-FYVE (Fab1, YOTB, Vac1 and EEA1)-containing protein 1 (DFCP1) has the capacity to bind to PI3P, but it is mostly associated with the ER (47). Under nutrient starvation conditions, DFCP1 forms a ring-like structure called an omegasome, which is regarded as a specialized region of the ER. Video microscopic analysis showed that autophagosome formation takes place inside the omegasome, which presumably acts as a scaffold; the autophagosome then moves out of the omegasome. A capacity to bind PI3P is critical in DFCP1 localization to the omegasome, which indicates that topical PI3P is generated in response to starvation (47). In addition to DFCP1, another PI3P-binding protein, WIPI-1 (WD repeat domain, phosphoinositide interacting 1), also co-localizes with LC3, although the functional significance is not known (48). Atg14L-bearing PI 3-kinase must be responsible for the PI3P generation around the omegasome or the autophagosome and the ER localization of Atg14L may be critical for its function.
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PI3P in bacterial sequestration |
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The role of PI3P in xenophagy has not been extensively pursued thus far. However, wortmannin, a potent PI 3-kinase inhibitor, inhibits GFP–LC3 recruitment to invaded Salmonella (21). Further, wortmannin treatment enhances Salmonella growth in invaded cells, similar to Atg5-knockout MEF cells (21, 49). Arg14L also catalyzes this reaction because its knockdown brings about a similar Salmonella phenotype (44).
Besides xenophagy, PI3P plays roles in the formation of a niche in host cells, called Salmonella-containing vacuoles (SCVs). It is believed that Salmonella that escape from SCVs are targeted to xenophagy after signaling through the production of reactive oxygen species (50). SopB is a Salmonella-originated phosphoinositide phosphatase secreted by a type III secretion system into the host cell cytosol just after the invasion. Although there are some contradicting reports, recently SopB was shown to decrease the amount of PI4, 5 P2 at the plasma membrane invasion area, and to recruit the endosomal small GTPase, Rab5, to the early SCV (51). Rab5 then recruits Vps34 (a PI 3-kinase) to the SCV and PI3P is generated (51). One of PI3P-biding proteins SNX1 (sorting nexin 1) is the downstream effecter of SCV-localized PI3P, and it acts in remodeling in the nascent SCV (52).
In the case of M. tuberculosis, it secretes the PI3-phosophatase, SapM (secreted acid phosphatase of M. tuberculosis), which inhibits the maturation of phagosomes (53). The connection between SCV-related PI3P and xenophagy-related PI3P is not known and is an interesting point to be pursued.
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Conclusion |
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In this review, we discussed representative Atg proteins as they relate to xenophagy. The discovery of xenophagy is a breakthrough, not only in the elucidation of a novel aspect of host–pathogen interactions, but also in the study of the canonical autophagy since it provides a different dimension of analysis of protein turnover. Further study should provide us a chance to develop potential treatments for the clinical aspects of xenophagy.
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Funding |
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The Ministry of Education, Culture, Sports, Science and Technology, Kakenhi (20113002).
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Abbreviations |
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| DFCP1, double-FYVE (Fab1, YOTB, Vac1 and EEA1)-containing protein 1 |
| ER, endoplasmic reticulum |
| GAS, Group A streptococci |
| GcAV, Group A streptococci-containing autophagic vacuole |
| GFP, green fluorescent protein |
| MEF, mouse embryo fibroblast |
| PE, phosphatidylethanolamine |
| PI3P, phosphatidylinositol 3-phosphate |
| PI 3-kinase, phosphatidylinositol 3-kinase |
| SCV, Salmonella-containing vacuole |
| SNP, single-nucleotide polymorphism |
| UVRAG, UV radiation resistance-associated gene |
| WD, tryptophan–aspartic acid |
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