Crosstalk between autophagy and inflammatory signalling pathways: balancing defence and homeostasis

Russell, R. C. et al. ULK1 induces autophagy by phosphorylating Beclin-1 and activating VPS34 lipid kinase. Nat. Cell Biol. 15, 741–750 (2013).

Ge, L., Melville, D., Zhang, M. & Schekman, R. The ER-Golgi intermediate compartment is a key membrane source for the LC3 lipidation step of autophagosome biogenesis. eLife 2, e00947 (2013).

Hamasaki, M. et al. Autophagosomes form at ER-mitochondria contact sites. Nature 495, 389–393 (2013).

Dooley, H. C. et al. WIPI2 links LC3 conjugation with PI3P, autophagosome formation, and pathogen clearance by recruiting Atg12-5-16L1. Mol. Cell 55, 238–252 (2014).

Randow, F. & Youle, R. J. Self and nonself: how autophagy targets mitochondria and bacteria. Cell Host Microbe 15, 403–411 (2014).

Choy, A. et al. The Legionella effector RavZ inhibits host autophagy through irreversible Atg8 deconjugation. Science 338, 1072–1076 (2012).This study provides an example of how intracellular bacteria block autophagy to evade trafficking to the lysosome.

Chen, Y. H. et al. Phosphatidylserine vesicles enable efficient en bloc transmission of enteroviruses. Cell 160, 619–630 (2015).

Martinez, J. et al. Molecular characterization of LC3-associated phagocytosis reveals distinct roles for Rubicon, NOX2 and autophagy proteins. Nat. Cell Biol. 17, 893–906 (2015).This study demonstrates that LAP is distinguished from autophagy by its dependence on rubicon and NADPH oxidase 2 (NOX2).

Zhao, Z. et al. Autophagosome-independent essential function for the autophagy protein Atg5 in cellular immunity to intracellular pathogens. Cell Host Microbe 4, 458–469 (2008).

Hwang, S. et al. Nondegradative role of Atg5-Atg12/ Atg16L1 autophagy protein complex in antiviral activity of interferon gamma. Cell Host Microbe 11, 397–409 (2012).

Choi, J. et al. The parasitophorous vacuole membrane of Toxoplasma gondii is targeted for disruption by ubiquitin-like conjugation systems of autophagy. Immunity 40, 924–935 (2014).

Selleck, E. M. et al. A noncanonical autophagy pathway restricts Toxoplasma gondii growth in a strain-specific manner in IFN-γ activated human cells. mBio 6, e01157–e01115 (2015).

Ohshima, J. et al. Role of mouse and human autophagy proteins in IFN-γ-induced cell-autonomous responses against Toxoplasma gondii. J. Immunol. 192, 3328–3335 (2014).

Haldar, A. K., Piro, A. S., Pilla, D. M., Yamamoto, M. & Coers, J. The E2-like conjugation enzyme Atg3 promotes binding of IRG and Gbp proteins to Chlamydia- and Toxoplasma-containing vacuoles and host resistance. PLoS ONE 9, e86684 (2014).

Park, S. et al. Targeting by Autophagy proteins (TAG): targeting of IFNγ-inducible GTPases to membranes by the LC3 conjugation system of autophagy. Autophagy 12, 1153–1167 (2016).

Shoji-Kawata, S. et al. Identification of a candidate therapeutic autophagy-inducing peptide. Nature 494, 201–206 (2013).This study shows that a cell-permeable beclin 1 peptide induces autophagy to enhance host defence.

Orvedahl, A. et al. Autophagy protects against Sindbis virus infection of the central nervous system. Cell Host Microbe 7, 115–127 (2010).

Kernbauer, E., Ding, Y. & Cadwell, K. An enteric virus can replace the beneficial function of commensal bacteria. Nature 516, 94–98 (2014).

Cadwell, K. et al. Virus-plus-susceptibility gene interaction determines Crohn's disease gene Atg16L1 phenotypes in intestine. Cell 141, 1135–1145 (2010).

Visvikis, O. et al. Innate host defense requires TFEB-mediated transcription of cytoprotective and antimicrobial genes. Immunity 40, 896–909 (2014).

Maurer, K. et al. Autophagy mediates tolerance to Staphylococcus aureus α-toxin. Cell Host Microbe 17, 429–440 (2015).This study shows that autophagy limits damage caused by a pore-forming toxin from a clinical isolate of S. aureus.

Figueiredo, N. et al. Anthracyclines induce DNA damage response-mediated protection against severe sepsis. Immunity 39, 874–884 (2013).

Medzhitov, R., Schneider, D. S. & Soares, M. P. Disease tolerance as a defense strategy. Science 335, 936–941 (2012).

Marchiando, A. M. et al. A deficiency in the autophagy gene Atg16L1 enhances resistance to enteric bacterial infection. Cell Host Microbe 14, 216–224 (2013).

Park, S. et al. Autophagy genes enhance murine gammaherpesvirus 68 reactivation from latency by preventing virus-induced systemic inflammation. Cell Host Microbe 19, 91–101 (2016).

Lu, Q. et al. Homeostatic control of innate lung inflammation by vici syndrome gene Epg5 and additional autophagy genes promotes influenza pathogenesis. Cell Host Microbe 19, 102–113 (2016).

Tattoli, I. et al. Amino acid starvation induced by invasive bacterial pathogens triggers an innate host defense program. Cell Host Microbe 11, 563–575 (2012).

Saitoh, T. et al. Loss of the autophagy protein Atg16L1 enhances endotoxin-induced IL-1β production. Nature 456, 264–268 (2008).This study is the first to demonstrate the immunosuppressive function of autophagy in limiting inflammasome activation.

Nakahira, K. et al. Autophagy proteins regulate innate immune responses by inhibiting the release of mitochondrial DNA mediated by the NALP3 inflammasome. Nat. Immunol. 12, 222–230 (2011).

Zhong, Z. et al. NF-κB restricts inflammasome activation via elimination of damaged mitochondria. Cell 164, 896–910 (2016).This study shows that mitophagy inhibits inflammasome activation in the presence of LPS.

Dupont, N. et al. Shigella phagocytic vacuolar membrane remnants participate in the cellular response to pathogen invasion and are regulated by autophagy. Cell Host Microbe 6, 137–149 (2009).

Meunier, E. et al. Caspase-11 activation requires lysis of pathogen-containing vacuoles by IFN-induced GTPases. Nature 509, 366–370 (2014).

Kreibich, S. et al. Autophagy proteins promote repair of endosomal membranes damaged by the Salmonella type three secretion system 1. Cell Host Microbe 18, 527–537 (2015).

Suzuki, T. et al. Differential regulation of caspase-1 activation, pyroptosis, and autophagy via Ipaf and ASC in Shigella-infected macrophages. PLoS Pathog. 3, e111 (2007).

Byrne, B. G., Dubuisson, J. F., Joshi, A. D., Persson, J. J. & Swanson, M. S. Inflammasome components coordinate autophagy and pyroptosis as macrophage responses to infection. mBio 4, e00620–00612 (2013).

Shi, C. S. et al. Activation of autophagy by inflammatory signals limits IL-1β production by targeting ubiquitinated inflammasomes for destruction. Nat. Immunol. 13, 255–263 (2012).

Bodemann, B. O. et al. RalB and the exocyst mediate the cellular starvation response by direct activation of autophagosome assembly. Cell 144, 253–267 (2011).

Ravindran, R. et al. The amino acid sensor GCN2 controls gut inflammation by inhibiting inflammasome activation. Nature 531, 523–527 (2016).

Wlodarska, M. et al. NLRP6 inflammasome orchestrates the colonic host-microbial interface by regulating goblet cell mucus secretion. Cell 156, 1045–1059 (2014).

Travassos, L. H. et al. Nod1 and Nod2 direct autophagy by recruiting ATG16L1 to the plasma membrane at the site of bacterial entry. Nat. Immunol. 11, 55–62 (2010).

Cooney, R. et al. NOD2 stimulation induces autophagy in dendritic cells influencing bacterial handling and antigen presentation. Nat. Med. 16, 90–97 (2010).

Homer, C. R. et al. A dual role for receptor-interacting protein kinase 2 (RIP2) kinase activity in nucleotide-binding oligomerization domain 2 (NOD2)-dependent autophagy. J. Biol. Chem. 287, 25565–25576 (2012).

Anand, P. K. et al. TLR2 and RIP2 pathways mediate autophagy of Listeria monocytogenes via extracellular signal-regulated kinase (ERK) activation. J. Biol. Chem. 286, 42981–42991 (2011).

Irving, A. T. et al. The immune receptor NOD1 and kinase RIP2 interact with bacterial peptidoglycan on early endosomes to promote autophagy and inflammatory signaling. Cell Host Microbe 15, 623–635 (2014).

Chauhan, S., Mandell, M. A. & Deretic, V. IRGM governs the core autophagy machinery to conduct antimicrobial defense. Mol. Cell 58, 507–521 (2015).

Plantinga, T. S. et al. Crohn's disease-associated ATG16L1 polymorphism modulates pro-inflammatory cytokine responses selectively upon activation of NOD2. Gut 60, 1229–1235 (2011).

Buffen, K. et al. Autophagy modulates Borrelia burgdorferi-induced production of interleukin-1β (IL-1β). J. Biol. Chem. 288, 8658–8666 (2013).

Lassen, K. G. et al. Atg16L1 T300A variant decreases selective autophagy resulting in altered cytokine signaling and decreased antibacterial defense. Proc. Natl Acad. Sci. USA 111, 7741–7746 (2014).

Murthy, A. et al. A Crohn's disease variant in Atg16l1 enhances its degradation by caspase 3. Nature 506, 456–462 (2014).

Lupfer, C. et al. Receptor interacting protein kinase 2-mediated mitophagy regulates inflammasome activation during virus infection. Nat. Immunol. 14, 480–488 (2013).

Wen, Z. et al. Neutrophils counteract autophagy-mediated anti-inflammatory mechanisms in alveolar macrophage: role in posthemorrhagic shock acute lung inflammation. J. Immunol. 193, 4623–4633 (2014).

Chu, H. et al. Gene-microbiota interactions contribute to the pathogenesis of inflammatory bowel disease. Science 352, 1116–1120 (2016).

Xu, Y. et al. Toll-like receptor 4 is a sensor for autophagy associated with innate immunity. Immunity 27, 135–144 (2007).

Delgado, M. A., Elmaoued, R. A., Davis, A. S., Kyei, G. & Deretic, V. Toll-like receptors control autophagy. EMBO J. 27, 1110–1121 (2008).

Shi, C. S. & Kehrl, J. H. TRAF6 and A20 regulate lysine 63-linked ubiquitination of Beclin-1 to control TLR4-induced autophagy. Sci. Signal. 3, ra42 (2010).

Meijer, A. H. & van der Vaart, M. DRAM1 promotes the targeting of mycobacteria to selective autophagy. Autophagy 10, 2389–2391 (2014).

Fujita, K., Maeda, D., Xiao, Q. & Srinivasula, S. M. Nrf2-mediated induction of p62 controls Toll-like receptor-4-driven aggresome-like induced structure formation and autophagic degradation. Proc. Natl Acad. Sci. USA 108, 1427–1432 (2011).

Wild, P. et al. Phosphorylation of the autophagy receptor optineurin restricts Salmonella growth. Science 333, 228–233 (2011).

Moy, R. H. et al. Antiviral autophagy restricts Rift Valley fever virus infection and is conserved from flies to mammals. Immunity 40, 51–65 (2014).

Benjamin, J. L., Sumpter, R. Jr., Levine, B. & Hooper, L. V. Intestinal epithelial autophagy is essential for host defense against invasive bacteria. Cell Host Microbe 13, 723–734 (2013).

Lee, H. K., Lund, J. M., Ramanathan, B., Mizushima, N. & Iwasaki, A. Autophagy-dependent viral recognition by plasmacytoid dendritic cells. Science 315, 1398–1401 (2007).

Henault, J. et al. Noncanonical autophagy is required for type I interferon secretion in response to DNA-immune complexes. Immunity 37, 986–997 (2012).

Sanjuan, M. A. et al. Toll-like receptor signalling in macrophages links the autophagy pathway to phagocytosis. Nature 450, 1253–1257 (2007).

Akoumianaki, T. et al. Aspergillus cell wall melanin blocks LC3-associated phagocytosis to promote pathogenicity. Cell Host Microbe 19, 79–90 (2016).

Katsuragi, Y. Ichimura, Y. & Komatsu, M. p62/SQSTM1 functions as a signaling hub and an autophagy adaptor. FEBS J. 282, 4672–4678 (2015).

Lee, H. M. et al. Autophagy negatively regulates keratinocyte inflammatory responses via scaffolding protein p62/SQSTM1. J. Immunol. 186, 1248–1258 (2011).

Kim, J. K. et al. MicroRNA-125a inhibits autophagy activation and antimicrobial responses during mycobacterial infection. J. Immunol. 194, 5355–5365 (2015).

Lei, Y. et al. The mitochondrial proteins NLRX1 and TUFM form a complex that regulates type I interferon and autophagy. Immunity 36, 933–946 (2012).

Xia, M. et al. Mitophagy enhances oncolytic measles virus replication by mitigating DDX58/RIG-I-like receptor signaling. J. Virol. 88, 5152–5164 (2014).

Zhao, Y. et al. COX5B regulates MAVS-mediated antiviral signaling through interaction with ATG5 and repressing ROS production. PLoS Pathog. 8, e1003086 (2012).

Tal, M. C. et al. Absence of autophagy results in reactive oxygen species-dependent amplification of RLR signaling. Proc. Natl Acad. Sci. USA 106, 2770–2775 (2009).

Jounai, N. et al. The Atg5–Atg12 conjugate associates with innate antiviral immune responses. Proc. Natl Acad. Sci. USA 104, 14050–14055 (2007).

Saitoh, T. et al. Atg9a controls dsDNA-driven dynamic translocation of STING and the innate immune response. Proc. Natl Acad. Sci. USA 106, 20842–20846 (2009).

Konno, H., Konno, K. & Barber, G. N. Cyclic dinucleotides trigger ULK1 (ATG1) phosphorylation of STING to prevent sustained innate immune signaling. Cell 155, 688–698 (2013).

Liang, Q. et al. Crosstalk between the cGAS DNA sensor and Beclin-1 autophagy protein shapes innate antimicrobial immune responses. Cell Host Microbe 15, 228–238 (2014).

Lan, Y. Y., Londono, D., Bouley, R., Rooney, M. S. & Hacohen, N. Dnase2a deficiency uncovers lysosomal clearance of damaged nuclear DNA via autophagy. Cell Rep. 9, 180–119 (2014).

Mathew, R. et al. Functional role of autophagy-mediated proteome remodeling in cell survival signaling and innate immunity. Mol. Cell 55, 916–930 (2014).

Grimm, W. A. et al. The Thr300Ala variant in ATG16L1 is associated with improved survival in human colorectal cancer and enhanced production of type I interferon. Gut 65, 456–464 (2016).

Gutierrez, M. G. et al. Autophagy is a defense mechanism inhibiting BCG and Mycobacterium tuberculosis survival in infected macrophages. Cell 119, 753–766 (2004).

Harris, J. et al. T helper 2 cytokines inhibit autophagic control of intracellular Mycobacterium tuberculosis. Immunity 27, 505–517 (2007).

Mostowy, S. et al. p62 and NDP52 proteins target intracytosolic Shigella and Listeria to different autophagy pathways. J. Biol. Chem. 286, 26987–26995 (2011).

Matsuzawa, T. et al. IFN-γ elicits macrophage autophagy via the p38 MAPK signaling pathway. J. Immunol. 189, 813–818 (2012).

Chang, Y. P. et al. Autophagy facilitates IFN-γ-induced Jak2-STAT1 activation and cellular inflammation. J. Biol. Chem. 285, 28715–28722 (2010).

Boonhok, R. et al. LAP-like process as an immune mechanism downstream of IFN-γ in control of the human malaria Plasmodium vivax liver stage. Proc. Natl Acad. Sci. USA 113, E3519–E3528 (2016).

Shen, S. et al. Cytoplasmic STAT3 represses autophagy by inhibiting PKR activity. Mol. Cell 48, 667–680 (2012).

Van Grol, J. et al. HIV-1 inhibits autophagy in bystander macrophage/monocytic cells through Src-Akt and STAT3. PLoS ONE 5, e11733 (2010).

Terawaki, S. et al. RUN and FYVE domain-containing protein 4 enhances autophagy and lysosome tethering in response to Interleukin-4. J. Cell Biol. 210, 1133–1152 (2015).

Dupont, N. et al. Autophagy-based unconventional secretory pathway for extracellular delivery of IL-1β. EMBO J. 30, 4701–4711 (2011).

Cullen, S. P., Kearney, C. J., Clancy, D. M. & Martin, S. J. Diverse activators of the NLRP3 inflammasome promote IL-1β secretion by triggering necrosis. Cell Rep. 11, 1535–1548 (2015).

Zhang, M., Kenny, S., Ge, L., Xu, K. & Schekman, R. Translocation of interleukin-1β into a vesicle intermediate in autophagy-mediated secretion. eLife 4, e11205 (2015).

Pilli, M. et al. TBK-1 promotes autophagy-mediated antimicrobial defense by controlling autophagosome maturation. Immunity 37, 223–234 (2012).

Castillo, E. F. et al. Autophagy protects against active tuberculosis by suppressing bacterial burden and inflammation. Proc. Natl Acad. Sci. USA 109, E3168–E3176 (2012).

Lee, J. P. et al. Loss of autophagy enhances MIF/macrophage migration inhibitory factor release by macrophages. Autophagy 12, 907–916 (2016).

Peral de Castro, C. et al. Autophagy regulates IL-23 secretion and innate T cell responses through effects on IL-1 secretion. J. Immunol. 189, 4144–4153 (2012).

Ding, Y. et al. Autophagy regulates TGF-β expression and suppresses kidney fibrosis induced by unilateral ureteral obstruction. J. Am. Soc. Nephrol. 25, 2835–2846 (2014).

Trinchieri, G. Type I interferon: friend or foe? J. Exp. Med. 207, 2053–2063 (2010).

Mello Pde, A. et al. Adenosine uptake is the major effector of extracellular ATP toxicity in human cervical cancer cells. Mol. Biol. Cell 25, 2905–2918 (2014).

Biswas, D. et al. ATP-induced autophagy is associated with rapid killing of intracellular mycobacteria within human monocytes/macrophages. BMC Immunol. 9, 35 (2008).

Takenouchi, T. et al. The activation of P2X7 receptor impairs lysosomal functions and stimulates the release of autophagolysosomes in microglial cells. J. Immunol. 182, 2051–2062 (2009).

Bian, S. et al. P2X7 integrates PI3K/AKT and AMPK-PRAS40-mTOR signaling pathways to mediate tumor cell death. PLoS ONE 8, e60184 (2013).

Martins, I. et al. Molecular mechanisms of ATP secretion during immunogenic cell death. Cell Death Differ. 21, 79–91 (2014).

Michaud, M. et al. Autophagy-dependent anticancer immune responses induced by chemotherapeutic agents in mice. Science 334, 1573–1577 (2011).This study demonstrates that autophagy promotes antitumour immunity by mediating the release of ATP.

Tang, D. et al. Endogenous HMGB1 regulates autophagy. J. Cell Biol. 190, 881–892 (2010).

Kang, R. et al. The receptor for advanced glycation end products (RAGE) sustains autophagy and limits apoptosis, promoting pancreatic tumor cell survival. Cell Death Differ. 17, 666–676 (2010).

Tang, D. et al. High-mobility group box 1 is essential for mitochondrial quality control. Cell. Metabolism 13, 701–711 (2011).

Zhu, X. et al. Cytosolic HMGB1 controls the cellular autophagy/apoptosis checkpoint during inflammation. J. Clin. Invest. 125, 1098–1110 (2015).

Yanai, H. et al. Conditional ablation of HMGB1 in mice reveals its protective function against endotoxemia and bacterial infection. Proc. Natl Acad. Sci. USA 110, 20699–20704 (2013).

Pua, H. H., Dzhagalov, I., Chuck, M., Mizushima, N. & He, Y. W. A critical role for the autophagy gene Atg5 in T cell survival and proliferation. J. Exp. Med. 204, 25–31 (2007).This study is the first to demonstrate that deficiency in an autophagy protein leads to defects in lymphocyte survival and proliferation.

Stephenson, L. M. et al. Identification of Atg5-dependent transcriptional changes and increases in mitochondrial mass in Atg5-deficient T lymphocytes. Autophagy 5, 625–635 (2009).

Jia, W. & He, Y. W. Temporal regulation of intracellular organelle homeostasis in T lymphocytes by autophagy. J. Immunol. 186, 5313–5322 (2011).

Kovacs, J. R. et al. Autophagy promotes T-cell survival through degradation of proteins of the cell death machinery. Cell Death Differ. 19, 144–152 (2012).

Pei, B. et al. Invariant NKT cells require autophagy to coordinate proliferation and survival signals during differentiation. J. Immunol. 194, 5872–5884 (2015).

Willinger, T. & Flavell, R. A. Canonical autophagy dependent on the class III phosphoinositide-3 kinase Vps34 is required for naive T-cell homeostasis. Proc. Natl Acad. Sci. USA 109, 8670–8675 (2012).

Matsuzawa, Y. et al. TNFAIP3 promotes survival of CD4 T cells by restricting MTOR and promoting autophagy. Autophagy 11, 1052–1062 (2015).

Xu, X. et al. Autophagy is essential for effector CD8+ T cell survival and memory formation. Nat. Immunol. 15, 1152–1161 (2014).

O'Sullivan, T. E., Johnson, L. R., Kang, H. H. & Sun, J. C. BNIP3- and BNIP3L-mediated mitophagy promotes the generation of natural killer cell memory. Immunity 43, 331–342 (2015).

Puleston, D. J. et al. Autophagy is a critical regulator of memory CD8+ T cell formation. eLife 3, e03706 (2014).

Schlie, K. et al. Survival of effector CD8+ T cells during influenza infection is dependent on autophagy. J. Immunol. 194, 4277–4286 (2015).

Henson, S. M. et al. p38 signaling inhibits mTORC1-independent autophagy in senescent human CD8+ T cells. J. Clin. Invest. 124, 4004–4016 (2014).

Hubbard, V. M. et al. Macroautophagy regulates energy metabolism during effector T cell activation. J. Immunol. 185, 7349–7357 (2010).

Miller, B. C. et al. The autophagy gene ATG5 plays an essential role in B lymphocyte development. Autophagy 4, 309–314 (2008).

Conway, K. L. et al. ATG5 regulates plasma cell differentiation. Autophagy 9, 528–537 (2013).

Pengo, N. et al. Plasma cells require autophagy for sustainable immunoglobulin production. Nat. Immunol. 14, 298–305 (2013).

Paul, S., Kashyap, A. K., Jia, W., He, Y. W. & Schaefer, B. C. Selective autophagy of the adaptor protein Bcl10 modulates T cell receptor activation of NF-κB. Immunity 36, 947–958 (2012).

Wei, J. et al. Autophagy enforces functional integrity of regulatory T cells by coupling environmental cues and metabolic homeostasis. Nat. Immunol. 17, 277–285 (2016).

Kabat, A. M. et al. The autophagy gene Atg16l1 differentially regulates Treg and TH2 cells to control intestinal inflammation. eLife 5, de12444 (2016).

Dengjel, J. et al. Autophagy promotes MHC class II presentation of peptides from intracellular source proteins. Proc. Natl Acad. Sci. USA 102, 7922–7927 (2005).

Nedjic, J., Aichinger, M., Emmerich, J., Mizushima, N. & Klein, L. Autophagy in thymic epithelium shapes the T-cell repertoire and is essential for tolerance. Nature 455, 396–400 (2008).

Ireland, J. M. & Unanue, E. R. Autophagy in antigen-presenting cells results in presentation of citrullinated peptides to CD4 T cells. J. Exp. Med. 208, 2625–2632 (2011).

Paludan, C. et al. Endogenous MHC class II processing of a viral nuclear antigen after autophagy. Science 307, 593–596 (2005).

Lee, Y. et al. p62 plays a specific role in interferon-γ-induced presentation of a Toxoplasma vacuolar antigen. Cell Rep. 13, 223–233 (2015).

Sakowski, E. T. et al. Ubiquilin 1 promotes IFN-γ-induced xenophagy of Mycobacterium tuberculosis. PLoS Pathog. 11, e1005076 (2015).

Romao, S. et al. Autophagy proteins stabilize pathogen-containing phagosomes for prolonged MHC II antigen processing. J. Cell Biol. 203, 757–766 (2013).

Martinez, J. et al. Microtubule-associated protein 1 light chain 3 alpha (LC3)-associated phagocytosis is required for the efficient clearance of dead cells. Proc. Natl Acad. Sci. USA 108, 17396–17401 (2011).

Brooks, C. R. et al. KIM-1-/TIM-1-mediated phagocytosis links ATG5-/ULK1-dependent clearance of apoptotic cells to antigen presentation. EMBO J. 34, 2441–2464 (2015).

Lee, H. K. et al. In vivo requirement for Atg5 in antigen presentation by dendritic cells. Immunity 32, 227–239 (2010).This study demonstrates that the autophagy pathway in DCs is crucial for antigen presentation during herpesvirus infection in vivo.

Gobeil, P. A. & Leib, D. A. Herpes simplex virus gamma34.5 interferes with autophagosome maturation and antigen presentation in dendritic cells. mBio 3, e00267–00212 (2012).

Ravindran, R. et al. Vaccine activation of the nutrient sensor GCN2 in dendritic cells enhances antigen presentation. Science 343, 313–317 (2014).This study shows that autophagy induced by the nutrient sensor GCN2 promotes cross-presentation of viral antigens.

Jostins, L. et al. Host–microbe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature 491, 119–124 (2012).

Cadwell, K. et al. A key role for autophagy and the autophagy gene Atg16l1 in mouse and human intestinal Paneth cells. Nature 456, 259–263 (2008).This study identifies a role for the autophagy gene ATG16L1 in supporting intestinal Paneth cells.

Patel, K. K. et al. Autophagy proteins control goblet cell function by potentiating reactive oxygen species production. EMBO J. 32, 3130–3144 (2013).

Adolph, T. E. et al. Paneth cells as a site of origin for intestinal inflammation. Nature 503, 272–276 (2013).

Conway, K. L. et al. Atg16l1 is required for autophagy in intestinal epithelial cells and protection of mice from Salmonella infection. Gastroenterology 145, 1347–1357 (2013).

Hubbard-Lucey, V. M. et al. Autophagy gene atg16l1 prevents lethal T cell alloreactivity mediated by dendritic cells. Immunity 41, 579–591 (2014).

Martin, L. J. et al. Functional variant in the autophagy-related 5 gene promotor is associated with childhood asthma. PLoS ONE 7, e33454 (2012).

Zhou, X. J. et al. Genetic association of PRDM1- ATG5 intergenic region and autophagy with systemic lupus erythematosus in a Chinese population. Ann. Rheumat. Diseases 70, 1330–1337 (2011).

Dickinson, J. D. et al. IL13 activates autophagy to regulate secretion in airway epithelial cells. Autophagy 12, 397–409 (2015).

Clarke, A. J. et al. Autophagy is activated in systemic lupus erythematosus and required for plasmablast development. Ann. Rheumat. Diseases 74, 912–920 (2015).

Alessandri, C. et al. T lymphocytes from patients with systemic lupus erythematosus are resistant to induction of autophagy. FASEB J. 26, 4722–4732 (2012).

Weindel, C. G. et al. B cell autophagy mediates TLR7-dependent autoimmunity and inflammation. Autophagy 11, 1010–1024 (2015).

Martinez, J. et al. Noncanonical autophagy inhibits the autoinflammatory, lupus-like response to dying cells. Nature 533, 115–119 (2016).

Huang, J. et al. Activation of antibacterial autophagy by NADPH oxidases. Proc. Natl Acad. Sci. USA 106, 6226–6231 (2009).

De Luca, A. et al. CD4+ T cell vaccination overcomes defective cross-presentation of fungal antigens in a mouse model of chronic granulomatous disease. J. Clin. Invest. 122, 1816–1831 (2012).

De Luca, A. et al. IL-1 receptor blockade restores autophagy and reduces inflammation in chronic granulomatous disease in mice and in humans. Proc. Natl Acad. Sci. USA 111, 3526–3531 (2014).

Schwerd, T. et al. Impaired antibacterial autophagy links granulomatous intestinal inflammation in Niemann-Pick disease type C1 and XIAP deficiency with NOD2 variants in Crohn's disease. Gut http://dx.doi.org/10.1136/gutjnl-2015-310382 (2016).

Luciani, A. et al. Defective CFTR induces aggresome formation and lung inflammation in cystic fibrosis through ROS-mediated autophagy inhibition. Nat. Cell Biol. 12, 863–875 (2010).

Abdulrahman, B. A. et al. Autophagy stimulation by rapamycin suppresses lung inflammation and infection by Burkholderia cenocepacia in a model of cystic fibrosis. Autophagy 7, 1359–1370 (2011).

Renna, M. et al. Azithromycin blocks autophagy and may predispose cystic fibrosis patients to mycobacterial infection. J. Clin. Invest. 121, 3554–3563 (2011).

Pyo, J. O. et al. Overexpression of Atg5 in mice activates autophagy and extends lifespan. Nature Commun. 4, 2300 (2013).

Starr, T. et al. Selective subversion of autophagy complexes facilitates completion of the Brucella intracellular cycle. Cell Host Microbe 11, 33–45 (2012).

Kimmey, J. M. et al. Unique role for ATG5 in neutrophil-mediated immunopathology during M. tuberculosis infection. Nature 528, 565–569 (2015).This study identifies a non-autophagy function of ATG5 in defence against M. tuberculosis.

Reggiori, F. et al. Coronaviruses hijack the LC3-I-positive EDEMosomes, ER-derived vesicles exporting short-lived ERAD regulators, for replication. Cell Host Microbe 7, 500–508 (2010).

Kageyama, S. et al. The LC3 recruitment mechanism is separate from Atg9L1-dependent membrane formation in the autophagic response against Salmonella. Mol. Biol. Cell 22, 2290–2300 (2011).

Sorbara, M. T. et al. The protein ATG16L1 suppresses inflammatory cytokines induced by the intracellular sensors Nod1 and Nod2 in an autophagy-independent manner. Immunity 39, 858–873 (2013).

Liu, E., Van Grol, J. & Subauste, C. S. Atg5 but not Atg7 in dendritic cells enhances IL-2 and IFN-γ production by Toxoplasma gondii-reactive CD4+ T cells. Microbes Infect. 17, 275–284 (2015).

Wellcome Trust Case Control Consortium. Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature 447, 661–678 (2007).

Cullup, T. et al. Recessive mutations in EPG5 cause Vici syndrome, a multisystem disorder with defective autophagy. Nat. Genet. 45, 83–87 (2013).

Hakonarson, H. et al. A genome-wide association study identifies KIAA0350 as a type 1 diabetes gene. Nature 448, 591–594 (2007).

Soleimanpour, S. A. et al. The diabetes susceptibility gene Clec16a regulates mitophagy. Cell 157, 1577–1590 (2014).

Schuster, C. et al. The autoimmunity-associated gene CLEC16A modulates thymic epithelial cell autophagy and alters T cell selection. Immunity 42, 942–952 (2015).

Smyth, D. J. et al. PTPN22 Trp620 explains the association of chromosome 1p13 with type 1 diabetes and shows a statistical interaction with HLA class II genotypes. Diabetes 57, 1730–1737 (2008).

Martinez, A. et al. Chromosomal region 16p13: further evidence of increased predisposition to immune diseases. Ann. Rheumat. Diseases 69, 309–311 (2010).

Scharl, M. et al. Crohn's disease-associated polymorphism within the PTPN2 gene affects muramyl-dipeptide-induced cytokine secretion and autophagy. Inflamm. Bowel Dis. 18, 900–912 (2012).

Yang, Z., Fujii, H., Mohan, S. V., Goronzy, J. J. & Weyand, C. M. Phosphofructokinase deficiency impairs ATP generation, autophagy, and redox balance in rheumatoid arthritis T cells. J. Exp. Med. 210, 2119–2134 (2013).