1932

Abstract

The cellular degradative pathway of autophagy has a fundamental role in immunity. Here, we review the function of autophagy and autophagy proteins in inflammation. We discuss how the autophagy machinery controls the burden of infectious agents while simultaneously limiting inflammatory pathologies, which often involves processes that are distinct from conventional autophagy. Among the newly emerging processes we describe are LC3-associated phagocytosis and targeting by autophagy proteins, both of which require many of the same proteins that mediate conventional autophagy. We also discuss how autophagy contributes to differentiation of myeloid and lymphoid cell types, coordinates multicellular immunity, and facilitates memory responses. Together, these functions establish an intimate link between autophagy, mucosal immunity, and chronic inflammatory diseases. Finally, we offer our perspective on current challenges and barriers to translation.

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2018-04-26
2024-04-17
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Literature Cited

  1. De Duve C, Wattiaux R. 1.  1966. Functions of lysosomes. Annu. Rev. Physiol. 28:435–92 [Google Scholar]
  2. Levine B, Klionsky DJ. 2.  2017. Autophagy wins the 2016 Nobel Prize in Physiology or Medicine: breakthroughs in baker's yeast fuel advances in biomedical research. PNAS 114:201–5 [Google Scholar]
  3. Hampe J, Franke A, Rosenstiel P, Till A, Teuber M. 3.  et al. 2007. A genome-wide association scan of nonsynonymous SNPs identifies a susceptibility variant for Crohn disease in ATG16L1. Nat. Genet. 39:207–11 [Google Scholar]
  4. Saitoh T, Fujita N, Jang MH, Uematsu S, Yang BG. 4.  et al. 2008. Loss of the autophagy protein Atg16L1 enhances endotoxin-induced IL-1β production. Nature 456:264–68 [Google Scholar]
  5. Cadwell K, Liu JY, Brown SL, Miyoshi H, Loh J. 5.  et al. 2008. A key role for autophagy and the autophagy gene Atg16l1 in mouse and human intestinal Paneth cells. Nature 456:259–63 [Google Scholar]
  6. Alers S, Loffler AS, Wesselborg S, Stork B. 6.  2012. Role of AMPK-mTOR-Ulk1/2 in the regulation of autophagy: cross talk, shortcuts, and feedbacks. Mol. Cell Biol. 32:2–11 [Google Scholar]
  7. Galluzzi L, Baehrecke EH, Ballabio A, Boya P, Bravo-San Pedro JM. 7.  et al. 2017. Molecular definitions of autophagy and related processes. EMBO J 36:1811–36 [Google Scholar]
  8. Hamasaki M, Furuta N, Matsuda A, Nezu A, Yamamoto A. 8.  et al. 2013. Autophagosomes form at ER-mitochondria contact sites. Nature 495:389–93 [Google Scholar]
  9. Ge L, Melville D, Zhang M, Schekman R. 9.  2013. The ER-Golgi intermediate compartment is a key membrane source for the LC3 lipidation step of autophagosome biogenesis. eLife 2:e00947 [Google Scholar]
  10. Dooley HC, Razi M, Polson HE, Girardin SE, Wilson MI, Tooze SA. 10.  2014. WIPI2 links LC3 conjugation with PI3P, autophagosome formation, and pathogen clearance by recruiting Atg12–5-16L1. Mol. Cell 55:238–52 [Google Scholar]
  11. Nishimura T, Kaizuka T, Cadwell K, Sahani MH, Saitoh T. 11.  et al. 2013. FIP200 regulates targeting of Atg16L1 to the isolation membrane. EMBO Rep 14:284–91 [Google Scholar]
  12. Tsuboyama K, Koyama-Honda I, Sakamaki Y, Koike M, Morishita H, Mizushima N. 12.  2016. The ATG conjugation systems are important for degradation of the inner autophagosomal membrane. Science 354:1036–41 [Google Scholar]
  13. Nguyen TN, Padman BS, Usher J, Oorschot V, Ramm G, Lazarou M. 13.  2016. Atg8 family LC3/GABARAP proteins are crucial for autophagosome-lysosome fusion but not autophagosome formation during PINK1/Parkin mitophagy and starvation. J. Cell Biol. 215:857–74 [Google Scholar]
  14. Jiang P, Nishimura T, Sakamaki Y, Itakura E, Hatta T. 14.  et al. 2014. The HOPS complex mediates autophagosome-lysosome fusion through interaction with syntaxin 17. Mol. Biol. Cell 25:1327–37 [Google Scholar]
  15. Khaminets A, Behl C, Dikic I. 15.  2016. Ubiquitin-dependent and independent signals in selective autophagy. Trends Cell Biol 26:6–16 [Google Scholar]
  16. Khaminets A, Heinrich T, Mari M, Grumati P, Huebner AK. 16.  et al. 2015. Regulation of endoplasmic reticulum turnover by selective autophagy. Nature 522:354–58 [Google Scholar]
  17. Mandell MA, Jain A, Arko-Mensah J, Chauhan S, Kimura T. 17.  et al. 2014. TRIM proteins regulate autophagy and can target autophagic substrates by direct recognition. Dev. Cell 30:394–409 [Google Scholar]
  18. Nakagawa I, Amano A, Mizushima N, Yamamoto A, Yamaguchi H. 18.  et al. 2004. Autophagy defends cells against invading group A Streptococcus. . Science 306:1037–40 [Google Scholar]
  19. Ogawa M, Yoshimori T, Suzuki T, Sagara H, Mizushima N, Sasakawa C. 19.  2005. Escape of intracellular Shigella from autophagy. Science 307:727–31 [Google Scholar]
  20. Birmingham CL, Smith AC, Bakowski MA, Yoshimori T, Brumell JH. 20.  2006. Autophagy controls Salmonella infection in response to damage to the Salmonella-containing vacuole. J. Biol. Chem. 281:11374–83 [Google Scholar]
  21. Yoshikawa Y, Ogawa M, Hain T, Yoshida M, Fukumatsu M. 21.  et al. 2009. Listeria monocytogenes ActA-mediated escape from autophagic recognition. Nat. Cell Biol. 11:1233–40 [Google Scholar]
  22. Orvedahl A, Sumpter R Jr., Xiao G, Ng A, Zou Z. 22.  et al. 2011. Image-based genome-wide siRNA screen identifies selective autophagy factors. Nature 480:113–17 [Google Scholar]
  23. Manzanillo PS, Ayres JS, Watson RO, Collins AC, Souza G. 23.  et al. 2013. The ubiquitin ligase parkin mediates resistance to intracellular pathogens. Nature 501:512–16 [Google Scholar]
  24. Huett A, Heath RJ, Begun J, Sassi SO, Baxt LA. 24.  et al. 2012. The LRR and RING domain protein LRSAM1 is an E3 ligase crucial for ubiquitin-dependent autophagy of intracellular Salmonella Typhimurium. Cell Host Microbe 12:778–90 [Google Scholar]
  25. Heath RJ, Goel G, Baxt LA, Rush JS, Mohanan V. 25.  et al. 2016. RNF166 determines recruitment of adaptor proteins during antibacterial autophagy. Cell Rep 17:2183–94 [Google Scholar]
  26. Fiskin E, Bionda T, Dikic I, Behrends C. 26.  2016. Global analysis of host and bacterial ubiquitinome in response to Salmonella Typhimurium infection. Mol. Cell 62:967–81 [Google Scholar]
  27. Franco LH, Nair VR, Scharn CR, Xavier RJ, Torrealba JR. 27.  et al. 2017. The ubiquitin ligase Smurf1 functions in selective autophagy of Mycobacterium tuberculosis and anti-tuberculous host defense. Cell Host Microbe 21:59–72 [Google Scholar]
  28. Otluvan Wijk SJL, Fricke F, Herhaus L, Gupta J, Hotte K. 28.  et al. 2017. Linear ubiquitination of cytosolic Salmonella Typhimurium activates NF-κB and restricts bacterial proliferation. Nat. Microbiol. 2:17066 [Google Scholar]
  29. Noad J, von der Malsburg A, Pathe C, Michel MA, Komander D, Randow F. 29.  2017. LUBAC-synthesized linear ubiquitin chains restrict cytosol-invading bacteria by activating autophagy and NF-κB. Nat. Microbiol. 2:17063 [Google Scholar]
  30. Thurston TL, Wandel MP, von Muhlinen N, Foeglein A, Randow F. 30.  2012. Galectin 8 targets damaged vesicles for autophagy to defend cells against bacterial invasion. Nature 482:414–18 [Google Scholar]
  31. Barnett TC, Liebl D, Seymour LM, Gillen CM, Lim JY. 31.  et al. 2013. The globally disseminated M1T1 clone of group A Streptococcus evades autophagy for intracellular replication. Cell Host Microbe 14:675–82 [Google Scholar]
  32. Choy A, Dancourt J, Mugo B, O'Connor TJ, Isberg RR. 32.  et al. 2012. The Legionella effector RavZ inhibits host autophagy through irreversible Atg8 deconjugation. Science 338:1072–76 [Google Scholar]
  33. Muniz-Feliciano L, Van Grol J Portillo JA, Liew L, Liu B. 33.  et al. 2013. Toxoplasma gondii-induced activation of EGFR prevents autophagy protein-mediated killing of the parasite. PLOS Pathog 9:e1003809 [Google Scholar]
  34. Tattoli I, Sorbara MT, Vuckovic D, Ling A, Soares F. 34.  et al. 2012. Amino acid starvation induced by invasive bacterial pathogens triggers an innate host defense program. Cell Host Microbe 11:563–75 [Google Scholar]
  35. Shi CS, Kehrl JH. 35.  2008. MyD88 and Trif target Beclin 1 to trigger autophagy in macrophages. J. Biol. Chem. 283:33175–82 [Google Scholar]
  36. Wild P, Farhan H, McEwan DG, Wagner S, Rogov VV. 36.  et al. 2011. Phosphorylation of the autophagy receptor optineurin restricts Salmonella growth. Science 333:228–33 [Google Scholar]
  37. Irving AT, Mimuro H, Kufer TA, Lo C, Wheeler R. 37.  et al. 2014. The immune receptor NOD1 and kinase RIP2 interact with bacterial peptidoglycan on early endosomes to promote autophagy and inflammatory signaling. Cell Host Microbe 15:623–35 [Google Scholar]
  38. Travassos LH, Carneiro LA, Ramjeet M, Hussey S, Kim YG. 38.  et al. 2010. Nod1 and Nod2 direct autophagy by recruiting ATG16L1 to the plasma membrane at the site of bacterial entry. Nat. Immunol. 11:55–62 [Google Scholar]
  39. Homer CR, Kabi A, Marina-Garcia N, Sreekumar A, Nesvizhskii AI. 39.  et al. 2012. A dual role for receptor-interacting protein kinase 2 (RIP2) kinase activity in nucleotide-binding oligomerization domain 2 (NOD2)-dependent autophagy. J. Biol. Chem. 287:25565–76 [Google Scholar]
  40. Cooney R, Baker J, Brain O, Danis B, Pichulik T. 40.  et al. 2010. NOD2 stimulation induces autophagy in dendritic cells influencing bacterial handling and antigen presentation. Nat. Med. 16:90–97 [Google Scholar]
  41. Chauhan S, Mandell MA, Deretic V. 41.  2015. IRGM governs the core autophagy machinery to conduct antimicrobial defense. Mol. Cell 58:507–21 [Google Scholar]
  42. Orvedahl A, MacPherson S, Sumpter R Jr., Talloczy Z, Zou Z, Levine B. 42.  2010. Autophagy protects against Sindbis virus infection of the central nervous system. Cell Host Microbe 7:115–27 [Google Scholar]
  43. Sumpter R Jr., Sirasanagandla S, Fernandez AF, Wei Y, Dong X. 43.  et al. 2016. Fanconi anemia proteins function in mitophagy and immunity. Cell 165:867–81 [Google Scholar]
  44. Lee MY, Sumpter R Jr., Zou Z, Sirasanagandla S, Wei Y. 44.  et al. 2017. Peroxisomal protein PEX13 functions in selective autophagy. EMBO Rep 18:48–60 [Google Scholar]
  45. Talloczy Z, Virgin HW 4th, Levine B. 45.  2006. PKR-dependent autophagic degradation of herpes simplex virus type 1. Autophagy 2:24–29 [Google Scholar]
  46. E X Hwang S, Oh S, Lee JS, Jeong JH. 46.  et al. 2009. Viral Bcl-2-mediated evasion of autophagy aids chronic infection of gammaherpesvirus 68. PLOS Pathog 5:e1000609 [Google Scholar]
  47. Campbell GR, Rawat P, Bruckman RS, Spector SA. 47.  2015. Human immunodeficiency virus type 1 Nef inhibits autophagy through transcription factor EB sequestration. PLOS Pathog 11:e1005018 [Google Scholar]
  48. Ribeiro CM, Sarrami-Forooshani R, Setiawan LC, Zijlstra-Willems EM, van Hamme JL. 48.  et al. 2016. Receptor usage dictates HIV-1 restriction by human TRIM5α in dendritic cell subsets. Nature 540:448–52 [Google Scholar]
  49. Staring J, von Castelmur E, Blomen VA, van den Hengel LG, Brockmann M. 49.  et al. 2017. PLA2G16 represents a switch between entry and clearance of Picornaviridae. Nature 541:412–16 [Google Scholar]
  50. Shoji-Kawata S, Sumpter R, Leveno M, Campbell GR, Zou Z. 50.  et al. 2013. Identification of a candidate therapeutic autophagy-inducing peptide. Nature 494:201–6 [Google Scholar]
  51. Starr T, Child R, Wehrly TD, Hansen B, Hwang S. 51.  et al. 2012. Selective subversion of autophagy complexes facilitates completion of the Brucella intracellular cycle. Cell Host Microbe 11:33–45 [Google Scholar]
  52. Romano PS, Arboit MA, Vazquez CL, Colombo MI. 52.  2009. The autophagic pathway is a key component in the lysosomal dependent entry of Trypanosoma cruzi into the host cell. Autophagy 5:6–18 [Google Scholar]
  53. Hansen MD, Johnsen IB, Stiberg KA, Sherstova T, Wakita T. 53.  et al. 2017. Hepatitis C virus triggers Golgi fragmentation and autophagy through the immunity-related GTPase M. PNAS 114:E3462–71 [Google Scholar]
  54. Shrivastava S, Bhanja Chowdhury J, Steele R, Ray R, Ray RB. 54.  2012. Hepatitis C virus upregulates Beclin1 for induction of autophagy and activates mTOR signaling. J. Virol. 86:8705–12 [Google Scholar]
  55. Wang L, Tian Y, Ou JH. 55.  2015. HCV induces the expression of Rubicon and UVRAG to temporally regulate the maturation of autophagosomes and viral replication. PLOS Pathog 11:e1004764 [Google Scholar]
  56. Huang H, Kang R, Wang J, Luo G, Yang W, Zhao Z. 56.  2013. Hepatitis C virus inhibits AKT-tuberous sclerosis complex (TSC), the mechanistic target of rapamycin (MTOR) pathway, through endoplasmic reticulum stress to induce autophagy. Autophagy 9:175–95 [Google Scholar]
  57. Wang J, Kang R, Huang H, Xi X, Wang B. 57.  et al. 2014. Hepatitis C virus core protein activates autophagy through EIF2AK3 and ATF6 UPR pathway-mediated MAP1LC3B and ATG12 expression. Autophagy 10:766–84 [Google Scholar]
  58. Dreux M, Gastaminza P, Wieland SF, Chisari FV. 58.  2009. The autophagy machinery is required to initiate hepatitis C virus replication. PNAS 106:14046–51 [Google Scholar]
  59. Fahmy AM, Labonte P. 59.  2017. The autophagy elongation complex (ATG5–12/16L1) positively regulates HCV replication and is required for wild-type membranous web formation. Sci. Rep. 7:40351 [Google Scholar]
  60. Mohl BP, Bartlett C, Mankouri J, Harris M. 60.  2016. Early events in the generation of autophagosomes are required for the formation of membrane structures involved in hepatitis C virus genome replication. J. Gen. Virol. 97:680–93 [Google Scholar]
  61. Shrivastava S, Devhare P, Sujijantarat N, Steele R, Kwon YC. 61.  et al. 2015. Knockdown of autophagy inhibits infectious hepatitis C virus release by the exosomal pathway. J. Virol. 90:1387–96 [Google Scholar]
  62. Alirezaei M, Flynn CT, Wood MR, Whitton JL. 62.  2012. Pancreatic acinar cell-specific autophagy disruption reduces coxsackievirus replication and pathogenesis in vivo. Cell Host Microbe 11:298–305 [Google Scholar]
  63. Wong J, Zhang J, Si X, Gao G, Mao I. 63.  et al. 2008. Autophagosome supports coxsackievirus B3 replication in host cells. J. Virol. 82:9143–53 [Google Scholar]
  64. Jackson WT, Giddings TH Jr., Taylor MP, Mulinyawe S, Rabinovitch M. 64.  et al. 2005. Subversion of cellular autophagosomal machinery by RNA viruses. PLOS Biol 3:e156 [Google Scholar]
  65. Chen Y-H, Du W, Hagemeijer MC, Takvorian PM, Pau C. 65.  et al. 2015. Phosphatidylserine vesicles enable efficient en bloc transmission of enteroviruses. Cell 160:619–30 [Google Scholar]
  66. Bird SW, Maynard ND, Covert MW, Kirkegaard K. 66.  2014. Nonlytic viral spread enhanced by autophagy components. PNAS 111:13081–86 [Google Scholar]
  67. Gutierrez MG, Master SS, Singh SB, Taylor GA, Colombo MI, Deretic V. 67.  2004. Autophagy is a defense mechanism inhibiting BCG and Mycobacterium tuberculosis survival in infected macrophages. Cell 119:753–66 [Google Scholar]
  68. Xu Y, Jagannath C, Liu XD, Sharafkhaneh A, Kolodziejska KE, Eissa NT. 68.  2007. Toll-like receptor 4 is a sensor for autophagy associated with innate immunity. Immunity 27:135–44 [Google Scholar]
  69. Delgado MA, Elmaoued RA, Davis AS, Kyei G, Deretic V. 69.  2008. Toll-like receptors control autophagy. EMBO J 27:1110–21 [Google Scholar]
  70. Sanjuan MA, Dillon CP, Tait SWG, Moshiach S, Dorsey F. 70.  et al. 2007. Toll-like receptor signalling in macrophages links the autophagy pathway to phagocytosis. Nature 450:1253–57 [Google Scholar]
  71. Martinez J, Malireddi RK, Lu Q, Cunha LD, Pelletier S. 71.  et al. 2015. Molecular characterization of LC3-associated phagocytosis reveals distinct roles for Rubicon, NOX2 and autophagy proteins. Nat. Cell Biol. 17:893–906 [Google Scholar]
  72. Tam JM, Mansour MK, Khan NS, Seward M, Puranam S. 72.  et al. 2014. Dectin-1-dependent LC3 recruitment to phagosomes enhances fungicidal activity in macrophages. J. Infect. Dis. 210:1844–54 [Google Scholar]
  73. Hubber A, Kubori T, Coban C, Matsuzawa T, Ogawa M. 73.  et al. 2017. Bacterial secretion system skews the fate of Legionella-containing vacuoles towards LC3-associated phagocytosis. Sci. Rep. 7:44795 [Google Scholar]
  74. Boonhok R, Rachaphaew N, Duangmanee A, Chobson P, Pattaradilokrat S. 74.  et al. 2016. LAP-like process as an immune mechanism downstream of IFN-γ in control of the human malaria Plasmodium vivax liver stage. PNAS 113:E3519–28 [Google Scholar]
  75. Oikonomou V, Moretti S, Renga G, Galosi C, Borghi M. 75.  et al. 2016. Noncanonical fungal autophagy inhibits inflammation in response to IFN-γ via DAPK1. Cell Host Microbe 20:744–57 [Google Scholar]
  76. Akoumianaki T, Kyrmizi I, Valsecchi I, Gresnigt MS, Samonis G. 76.  et al. 2016. Aspergillus cell wall melanin blocks LC3-associated phagocytosis to promote pathogenicity. Cell Host Microbe 19:79–90 [Google Scholar]
  77. Park S, Choi J, Biering SB, Dominici E, Williams LE, Hwang S. 77.  2016. Targeting by AutophaGy proteins (TAG): targeting of IFNG-inducible GTPases to membranes by the LC3 conjugation system of autophagy. Autophagy 12:1153–67 [Google Scholar]
  78. Zhao Z, Fux B, Goodwin M, Dunay IR, Strong D. 78.  et al. 2008. Autophagosome-independent essential function for the autophagy protein Atg5 in cellular immunity to intracellular pathogens. Cell Host Microbe 4:458–69 [Google Scholar]
  79. Choi J, Park S, Biering SB, Selleck E, Liu CY. 79.  et al. 2014. The parasitophorous vacuole membrane of Toxoplasma gondii is targeted for disruption by ubiquitin-like conjugation systems of autophagy. Immunity 40:924–35 [Google Scholar]
  80. Haldar AK, Piro AS, Pilla DM, Yamamoto M, Coers J. 80.  2014. 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 [Google Scholar]
  81. Ohshima J, Lee Y, Sasai M, Saitoh T, Su Ma J. 81.  et al. 2014. Role of mouse and human autophagy proteins in IFN-γ-induced cell-autonomous responses against Toxoplasma gondii. . J. Immunol. 192:3328–35 [Google Scholar]
  82. Selleck EM, Orchard RC, Lassen KG, Beatty WL, Xavier RJ. 82.  et al. 2015. A noncanonical autophagy pathway restricts Toxoplasma gondii growth in a strain-specific manner in IFN-γ-activated human cells. mBio 6:e01157–e15 [Google Scholar]
  83. Sasai M, Sakaguchi N, Ma JS, Nakamura S, Kawabata T. 83.  et al. 2017. Essential role for GABARAP autophagy proteins in interferon-inducible GTPase-mediated host defense. Nat. Immunol. 18:899–91 [Google Scholar]
  84. Hwang S, Maloney NS, Bruinsma MW, Goel G, Duan E. 84.  et al. 2012. Nondegradative role of Atg5-Atg12/ Atg16L1 autophagy protein complex in antiviral activity of interferon gamma. Cell Host Microbe 11:397–409 [Google Scholar]
  85. Biering SB, Choi J, Halstrom RA, Brown HM, Beatty WL. 85.  et al. 2017. Viral replication complexes are targeted by LC3-guided interferon-inducible GTPases. Cell Host Microbe 22:74–85.e7 [Google Scholar]
  86. Dupont N, Jiang S, Pilli M, Ornatowski W, Bhattacharya D, Deretic V. 86.  2011. Autophagy-based unconventional secretory pathway for extracellular delivery of IL-1β. EMBO J 30:4701–11 [Google Scholar]
  87. Kimura T, Jia J, Kumar S, Choi SW, Gu Y. 87.  et al. 2017. Dedicated SNAREs and specialized TRIM cargo receptors mediate secretory autophagy. EMBO J 36:42–60 [Google Scholar]
  88. Zhang M, Kenny SJ, Ge L, Xu K, Schekman R. 88.  2015. Translocation of interleukin-1β into a vesicle intermediate in autophagy-mediated secretion. eLife 4:e11205 [Google Scholar]
  89. Miao Y, Li G, Zhang X, Xu H, Abraham SN. 89.  2015. A TRP Channel senses lysosome neutralization by pathogens to trigger their expulsion. Cell 161:1306–19 [Google Scholar]
  90. DeSelm CJ, Miller BC, Zou W, Beatty WL, van Meel E. 90.  et al. 2011. Autophagy proteins regulate the secretory component of osteoclastic bone resorption. Dev. Cell 21:966–74 [Google Scholar]
  91. Ushio H, Ueno T, Kojima Y, Komatsu M, Tanaka S. 91.  et al. 2011. Crucial role for autophagy in degranulation of mast cells. J. Allergy Clin. Immunol. 127:1267–76.e6 [Google Scholar]
  92. Patel KK, Miyoshi H, Beatty WL, Head RD, Malvin NP. 92.  et al. 2013. Autophagy proteins control goblet cell function by potentiating reactive oxygen species production. EMBO J 32:3130–44 [Google Scholar]
  93. Wlodarska M, Thaiss CA, Nowarski R, Henao-Mejia J, Zhang JP. 93.  et al. 2014. NLRP6 inflammasome orchestrates the colonic host-microbial interface by regulating goblet cell mucus secretion. Cell 156:1045–59 [Google Scholar]
  94. Watson RO, Manzanillo PS, Cox JS. 94.  2012. Extracellular M. tuberculosis DNA targets bacteria for autophagy by activating the host DNA-sensing pathway. Cell 150:803–15 [Google Scholar]
  95. Castillo EF, Dekonenko A, Arko-Mensah J, Mandell MA, Dupont N. 95.  et al. 2012. Autophagy protects against active tuberculosis by suppressing bacterial burden and inflammation. PNAS 109:E3168–76 [Google Scholar]
  96. Kimmey JM, Huynh JP, Weiss LA, Park S, Kambal A. 96.  et al. 2015. Unique role for ATG5 in neutrophil-mediated immunopathology during M. tuberculosis infection. Nature 528:565–69 [Google Scholar]
  97. Mauthe M, Langereis M, Jung J, Zhou X, Jones A. 97.  et al. 2016. An siRNA screen for ATG protein depletion reveals the extent of the unconventional functions of the autophagy proteome in virus replication. J. Cell Biol. 214:619–35 [Google Scholar]
  98. Jacquel A, Obba S, Boyer L, Dufies M, Robert G. 98.  et al. 2012. Autophagy is required for CSF-1-induced macrophagic differentiation and acquisition of phagocytic functions. Blood 119:4527–31 [Google Scholar]
  99. Obba S, Hizir Z, Boyer L, Selimoglu-Buet D, Pfeifer A. 99.  et al. 2015. The PRKAA1/AMPKα1 pathway triggers autophagy during CSF1-induced human monocyte differentiation and is a potential target in CMML. Autophagy 11:1114–29 [Google Scholar]
  100. Zhang Y, Morgan MJ, Chen K, Choksi S, Liu ZG. 100.  2012. Induction of autophagy is essential for monocyte-macrophage differentiation. Blood 119:2895–905 [Google Scholar]
  101. Stranks AJ, Hansen AL, Panse I, Mortensen M, Ferguson DJ. 101.  et al. 2015. Autophagy controls acquisition of aging features in macrophages. J. Innate Immun. 7:375–91 [Google Scholar]
  102. Lee JP, Foote A, Fan H, Peral de Castro C, Lang T. 102.  et al. 2016. Loss of autophagy enhances MIF/macrophage migration inhibitory factor release by macrophages. Autophagy 12:907–16 [Google Scholar]
  103. Tal MC, Sasai M, Lee HK, Yordy B, Shadel GS, Iwasaki A. 103.  2009. Absence of autophagy results in reactive oxygen species-dependent amplification of RLR signaling. PNAS 106:2770–75 [Google Scholar]
  104. Castillo EF, Dekonenko A, Arko-Mensah J, Mandell MA, Dupont N. 104.  et al. 2012. Autophagy protects against active tuberculosis by suppressing bacterial burden and inflammation. PNAS 109:E3168–76 [Google Scholar]
  105. Esteban-Martinez L, Sierra-Filardi E, McGreal RS, Salazar-Roa M, Marino G. 105.  et al. 2017. Programmed mitophagy is essential for the glycolytic switch during cell differentiation. EMBO J 36:1688–706 [Google Scholar]
  106. Ip WKE, Hoshi N, Shouval DS, Snapper S, Medzhitov R. 106.  2017. Anti-inflammatory effect of IL-10 mediated by metabolic reprogramming of macrophages. Science 356:513–19 [Google Scholar]
  107. Nimmerjahn F, Milosevic S, Behrends U, Jaffee EM, Pardoll DM. 107.  et al. 2003. Major histocompatibility complex class II-restricted presentation of a cytosolic antigen by autophagy. Eur. J. Immunol. 33:1250–59 [Google Scholar]
  108. Dorfel D, Appel S, Grunebach F, Weck MM, Muller MR. 108.  et al. 2005. Processing and presentation of HLA class I and II epitopes by dendritic cells after transfection with in vitro-transcribed MUC1 RNA. Blood 105:3199–205 [Google Scholar]
  109. Paludan C, Schmid D, Landthaler M, Vockerodt M, Kube D. 109.  et al. 2005. Endogenous MHC class II processing of a viral nuclear antigen after autophagy. Science 307:593–96 [Google Scholar]
  110. Schmid D, Pypaert M, Munz C. 110.  2007. Antigen-loading compartments for major histocompatibility complex class II molecules continuously receive input from autophagosomes. Immunity 26:79–92 [Google Scholar]
  111. Lee HK, Mattei LM, Steinberg BE, Alberts P, Lee YH. 111.  et al. 2010. In vivo requirement for Atg5 in antigen presentation by dendritic cells. Immunity 32:227–39 [Google Scholar]
  112. Ravindran R, Khan N, Nakaya HI, Li S, Loebbermann J. 112.  et al. 2014. Vaccine activation of the nutrient sensor GCN2 in dendritic cells enhances antigen presentation. Science 343:313–17 [Google Scholar]
  113. Li H, Li Y, Jiao J, Hu HM. 113.  2011. Alpha-alumina nanoparticles induce efficient autophagy-dependent cross-presentation and potent antitumour response. Nat. Nanotechnol. 6:645–50 [Google Scholar]
  114. Uhl M, Kepp O, Jusforgues-Saklani H, Vicencio JM, Kroemer G, Albert ML. 114.  2009. Autophagy within the antigen donor cell facilitates efficient antigen cross-priming of virus-specific CD8+ T cells. Cell Death Differ 16:991–1005 [Google Scholar]
  115. Mintern JD, Macri C, Chin WJ, Panozza SE, Segura E. 115.  et al. 2015. Differential use of autophagy by primary dendritic cells specialized in cross-presentation. Autophagy 11:906–17 [Google Scholar]
  116. Khan N, Vidyarthi A, Pahari S, Negi S, Aqdas M. 116.  et al. 2016. Signaling through NOD-2 and TLR-4 bolsters the T cell priming capability of dendritic cells by inducing autophagy. Sci. Rep. 6:19084 [Google Scholar]
  117. Jagannath C, Lindsey DR, Dhandayuthapani S, Xu Y, Hunter RL Jr., Eissa NT. 117.  2009. Autophagy enhances the efficacy of BCG vaccine by increasing peptide presentation in mouse dendritic cells. Nat. Med. 15:267–76 [Google Scholar]
  118. Terawaki S, Camosseto V, Prete F, Wenger T, Papadopoulos A. 118.  et al. 2015. RUN and FYVE domain–containing protein 4 enhances autophagy and lysosome tethering in response to interleukin-4. J. Cell Biol. 210:1133–52 [Google Scholar]
  119. Loi M, Muller A, Steinbach K, Niven J, Barreira da Silva R. 119.  et al. 2016. Macroautophagy proteins control MHC class I levels on dendritic cells and shape anti-viral CD8+ T cell responses. Cell Rep 15:1076–87 [Google Scholar]
  120. Hubbard-Lucey VM, Shono Y, Maurer K, West ML, Singer NV. 120.  et al. 2014. Autophagy gene atg16l1 prevents lethal T cell alloreactivity mediated by dendritic cells. Immunity 41:579–91 [Google Scholar]
  121. Alissafi T, Banos A, Boon L, Sparwasser T, Ghigo A. 121.  et al. 2017. Tregs restrain dendritic cell autophagy to ameliorate autoimmunity. J. Clin. Investig. 127:2789–804 [Google Scholar]
  122. Lee HK, Lund JM, Ramanathan B, Mizushima N, Iwasaki A. 122.  2007. Autophagy-dependent viral recognition by plasmacytoid dendritic cells. Science 315:1398–401 [Google Scholar]
  123. Peral de Castro C, Jones SA, Ni Cheallaigh C, Hearnden CA, Williams L. 123.  et al. 2012. Autophagy regulates IL-23 secretion and innate T cell responses through effects on IL-1 secretion. J. Immunol. 189:4144–53 [Google Scholar]
  124. Romao S, Gasser N, Becker AC, Guhl B, Bajagic M. 124.  et al. 2013. Autophagy proteins stabilize pathogen-containing phagosomes for prolonged MHC II antigen processing. J. Cell Biol. 203:757–66 [Google Scholar]
  125. Mitroulis I, Kourtzelis I, Kambas K, Rafail S, Chrysanthopoulou A. 125.  et al. 2010. Regulation of the autophagic machinery in human neutrophils. Eur. J. Immunol. 40:1461–72 [Google Scholar]
  126. Bhattacharya A, Wei Q, Shin JN, Abdel Fattah E, Bonilla DL. 126.  et al. 2015. autophagy is required for neutrophil-mediated inflammation. Cell Rep 12:1731–39 [Google Scholar]
  127. Remijsen Q, Vanden Berghe T, Wirawan E, Asselbergh B, Parthoens E. 127.  et al. 2011. Neutrophil extracellular trap cell death requires both autophagy and superoxide generation. Cell Res 21:290–304 [Google Scholar]
  128. Kambas K, Mitroulis I, Apostolidou E, Girod A, Chrysanthopoulou A. 128.  et al. 2012. Autophagy mediates the delivery of thrombogenic tissue factor to neutrophil extracellular traps in human sepsis. PLOS ONE 7:e45427 [Google Scholar]
  129. Yousefi S, Perozzo R, Schmid I, Ziemiecki A, Schaffner T. 129.  et al. 2006. Calpain-mediated cleavage of Atg5 switches autophagy to apoptosis. Nat. Cell Biol. 8:1124–32 [Google Scholar]
  130. Pua HH, Dzhagalov I, Chuck M, Mizushima N, He YW. 130.  2007. A critical role for the autophagy gene Atg5 in T cell survival and proliferation. J. Exp. Med. 204:25–31 [Google Scholar]
  131. Stephenson LM, Miller BC, Ng A, Eisenberg J, Zhao Z. 131.  et al. 2009. Identification of Atg5-dependent transcriptional changes and increases in mitochondrial mass in Atg5-deficient T lymphocytes. Autophagy 5:625–35 [Google Scholar]
  132. Pua HH, Guo J, Komatsu M, He YW. 132.  2009. Autophagy is essential for mitochondrial clearance in mature T lymphocytes. J. Immunol. 182:4046–55 [Google Scholar]
  133. Jia W, He YW. 133.  2011. Temporal regulation of intracellular organelle homeostasis in T lymphocytes by autophagy. J. Immunol. 186:5313–22 [Google Scholar]
  134. Willinger T, Flavell RA. 134.  2012. Canonical autophagy dependent on the class III phosphoinositide-3 kinase Vps34 is required for naive T-cell homeostasis. PNAS 109:8670–75 [Google Scholar]
  135. Pei B, Zhao M, Miller BC, Vela JL, Bruinsma MW. 135.  et al. 2015. Invariant NKT cells require autophagy to coordinate proliferation and survival signals during differentiation. J. Immunol. 194:5872–84 [Google Scholar]
  136. O'Sullivan TE, Johnson LR, Kang HH, Sun JC. 136.  2015. BNIP3- and BNIP3L-mediated mitophagy promotes the generation of natural killer cell memory. Immunity 43:331–42 [Google Scholar]
  137. O'Sullivan TE, Geary CD, Weizman OE, Geiger TL, Rapp M. 137.  et al. 2016. Atg5 is essential for the development and survival of innate lymphocytes. Cell Rep 15:1910–19 [Google Scholar]
  138. Matsuzawa Y, Oshima S, Takahara M, Maeyashiki C, Nemoto Y. 138.  et al. 2015. TNFAIP3 promotes survival of CD4 T cells by restricting MTOR and promoting autophagy. Autophagy 11:1052–62 [Google Scholar]
  139. Hubbard VM, Valdor R, Patel B, Singh R, Cuervo AM, Macian F. 139.  2010. Macroautophagy regulates energy metabolism during effector T cell activation. J. Immunol. 185:7349–57 [Google Scholar]
  140. Whang MI, Tavares RM, Benjamin DI, Kattah MG, Advincula R. 140.  et al. 2017. The ubiquitin binding protein TAX1BP1 mediates autophagasome induction and the metabolic transition of activated T cells. Immunity 46:405–20 [Google Scholar]
  141. Wei J, Long L, Yang K, Guy C, Shrestha S. 141.  et al. 2016. Autophagy enforces functional integrity of regulatory T cells by coupling environmental cues and metabolic homeostasis. Nat. Immunol. 17:277–85 [Google Scholar]
  142. Jia W, He MX, McLeod IX, Guo J, Ji D, He YW. 142.  2015. Autophagy regulates T lymphocyte proliferation through selective degradation of the cell-cycle inhibitor CDKN1B/p27Kip1. Autophagy 11:2335–45 [Google Scholar]
  143. Xu X, Araki K, Li S, Han JH, Ye L. 143.  et al. 2014. Autophagy is essential for effector CD8+ T cell survival and memory formation. Nat. Immunol. 15:1152–61 [Google Scholar]
  144. Puleston DJ, Zhang H, Powell TJ, Lipina E, Sims S. 144.  et al. 2014. Autophagy is a critical regulator of memory CD8+ T cell formation. eLife 3:e03706 [Google Scholar]
  145. Valdor R, Mocholi E, Botbol Y, Guerrero-Ros I, Chandra D. 145.  et al. 2014. Chaperone-mediated autophagy regulates T cell responses through targeted degradation of negative regulators of T cell activation. Nat. Immunol. 15:1046–54 [Google Scholar]
  146. Miller BC, Zhao Z, Stephenson LM, Cadwell K, Pua HH. 146.  et al. 2008. The autophagy gene ATG5 plays an essential role in B lymphocyte development. Autophagy 4:309–14 [Google Scholar]
  147. Pengo N, Scolari M, Oliva L, Milan E, Mainoldi F. 147.  et al. 2013. Plasma cells require autophagy for sustainable immunoglobulin production. Nat. Immunol. 14:298–305 [Google Scholar]
  148. Conway KL, Kuballa P, Khor B, Zhang M, Shi HN. 148.  et al. 2013. ATG5 regulates plasma cell differentiation. Autophagy 9:528–37 [Google Scholar]
  149. Chen M, Hong MJ, Sun H, Wang L, Shi X. 149.  et al. 2014. Essential role for autophagy in the maintenance of immunological memory against influenza infection. Nat. Med. 20:503–10 [Google Scholar]
  150. Chen M, Kodali S, Jang A, Kuai L, Wang J. 150.  2015. Requirement for autophagy in the long-term persistence but not initial formation of memory B cells. J. Immunol. 194:2607–15 [Google Scholar]
  151. Martinez-Martin N, Maldonado P, Gasparrini F, Frederico B, Aggarwal S. 151.  et al. 2017. A switch from canonical to noncanonical autophagy shapes B cell responses. Science 355:641–47 [Google Scholar]
  152. Zhong Z, Umemura A, Sanchez-Lopez E, Liang S, Shalapour S. 152.  et al. 2016. NF-κB restricts inflammasome activation via elimination of damaged mitochondria. Cell 164:896–910 [Google Scholar]
  153. Lupfer C, Thomas PG, Anand PK, Vogel P, Milasta S. 153.  et al. 2013. Receptor interacting protein kinase 2–mediated mitophagy regulates inflammasome activation during virus infection. Nat. Immunol. 14:480–88 [Google Scholar]
  154. Nakahira K, Haspel JA, Rathinam VA, Lee SJ, Dolinay T. 154.  et al. 2011. Autophagy proteins regulate innate immune responses by inhibiting the release of mitochondrial DNA mediated by the NALP3 inflammasome. Nat. Immunol. 12:222–30 [Google Scholar]
  155. Ravindran R, Loebbermann J, Nakaya HI, Khan N, Ma H. 155.  et al. 2016. The amino acid sensor GCN2 controls gut inflammation by inhibiting inflammasome activation. Nature 531:523–27 [Google Scholar]
  156. Dupont N, Lacas-Gervais S, Bertout J, Paz I, Freche B. 156.  et al. 2009. Shigella phagocytic vacuolar membrane remnants participate in the cellular response to pathogen invasion and are regulated by autophagy. Cell Host Microbe 6:137–49 [Google Scholar]
  157. Meunier E, Dick MS, Dreier RF, Schurmann N, Kenzelmann Broz D. 157.  et al. 2014. Caspase-11 activation requires lysis of pathogen-containing vacuoles by IFN-induced GTPases. Nature 509:366–70 [Google Scholar]
  158. Shi CS, Shenderov K, Huang NN, Kabat J, Abu-Asab M. 158.  et al. 2012. Activation of autophagy by inflammatory signals limits IL-1β production by targeting ubiquitinated inflammasomes for destruction. Nat. Immunol. 13:255–63 [Google Scholar]
  159. Liang Q, Seo GJ, Choi YJ, Kwak MJ, Ge J. 159.  et al. 2014. Crosstalk between the cGAS DNA sensor and Beclin-1 autophagy protein shapes innate antimicrobial immune responses. Cell Host Microbe 15:228–38 [Google Scholar]
  160. Saitoh T, Fujita N, Hayashi T, Takahara K, Satoh T. 160.  et al. 2009. Atg9a controls dsDNA-driven dynamic translocation of STING and the innate immune response. PNAS 106:20842–46 [Google Scholar]
  161. Konno H, Konno K, Barber GN. 161.  2013. Cyclic dinucleotides trigger ULK1 (ATG1) phosphorylation of STING to prevent sustained innate immune signaling. Cell 155:688–98 [Google Scholar]
  162. Lei Y, Wen H, Yu Y, Taxman DJ, Zhang L. 162.  et al. 2012. The mitochondrial proteins NLRX1 and TUFM form a complex that regulates type I interferon and autophagy. Immunity 36:933–46 [Google Scholar]
  163. Zhao Y, Sun X, Nie X, Sun L, Tang TS. 163.  et al. 2012. COX5B regulates MAVS-mediated antiviral signaling through interaction with ATG5 and repressing ROS production. PLOS Pathog 8:e1003086 [Google Scholar]
  164. Mathew R, Khor S, Hackett SR, Rabinowitz JD, Perlman DH, White E. 164.  2014. Functional role of autophagy-mediated proteome remodeling in cell survival signaling and innate immunity. Mol. Cell 55:916–30 [Google Scholar]
  165. Ding B, Zhang L, Li Z, Zhong Y, Tang Q. 165.  et al. 2017. The matrix protein of human parainfluenza virus type 3 induces mitophagy that suppresses interferon responses. Cell Host Microbe 21:538–47.e4 [Google Scholar]
  166. Kuo SM, Chen CJ, Chang SC, Liu TJ, Chen YH. 166.  et al. 2017. Inhibition of avian influenza A virus replication in human cells by host restriction factor TUFM is correlated with autophagy. mBio 8:e00481–17 [Google Scholar]
  167. Xia M, Gonzalez P, Li C, Meng G, Jiang A. 166a.  et al. 2014. Mitophagy enhances oncolytic measles virus replication by mitigating DDX58/RIG-I-like receptor signaling. J. Virol. 88:5152–64 [Google Scholar]
  168. Jounai N, Takeshita F, Kobiyama K, Sawano A, Miyawaki A. 167.  et al. 2007. The Atg5–Atg12 conjugate associates with innate antiviral immune responses. PNAS 104:14050–55 [Google Scholar]
  169. Marino G, Niso-Santano M, Baehrecke EH, Kroemer G. 168.  2014. Self-consumption: the interplay of autophagy and apoptosis. Nat. Rev. Mol. Cell Biol. 15:81–94 [Google Scholar]
  170. Boya P, Gonzalez-Polo RA, Casares N, Perfettini JL, Dessen P. 169.  et al. 2005. Inhibition of macroautophagy triggers apoptosis. Mol. Cell Biol. 25:1025–40 [Google Scholar]
  171. Hou W, Han J, Lu C, Goldstein LA, Rabinowich H. 170.  2010. Autophagic degradation of active caspase-8: a crosstalk mechanism between autophagy and apoptosis. Autophagy 6:891–900 [Google Scholar]
  172. Amir M, Zhao E, Fontana L, Rosenberg H, Tanaka K. 171.  et al. 2013. Inhibition of hepatocyte autophagy increases tumor necrosis factor-dependent liver injury by promoting caspase-8 activation. Cell Death Differ 20:878–87 [Google Scholar]
  173. Suzuki T, Franchi L, Toma C, Ashida H, Ogawa M. 172.  et al. 2007. Differential regulation of caspase-1 activation, pyroptosis, and autophagy via Ipaf and ASC in Shigella-infected macrophages. PLOS Pathog 3:e111 [Google Scholar]
  174. Byrne BG, Dubuisson JF, Joshi AD, Persson JJ, Swanson MS. 173.  2013. Inflammasome components coordinate autophagy and pyroptosis as macrophage responses to infection. mBio 4:e00620–12 [Google Scholar]
  175. Liu Y, Shoji-Kawata S, Sumpter RM Jr., Wei Y, Ginet V. 174.  et al. 2013. Autosis is a Na+,K+-ATPase-regulated form of cell death triggered by autophagy-inducing peptides, starvation, and hypoxia-ischemia. PNAS 110:20364–71 [Google Scholar]
  176. Goodall ML, Fitzwalter BE, Zahedi S, Wu M, Rodriguez D. 175.  et al. 2016. The autophagy machinery controls cell death switching between apoptosis and necroptosis. Dev. Cell 37:337–49 [Google Scholar]
  177. Mizumura K, Cloonan SM, Nakahira K, Bhashyam AR, Cervo M. 176.  et al. 2014. Mitophagy-dependent necroptosis contributes to the pathogenesis of COPD. J. Clin. Investig. 124:3987–4003 [Google Scholar]
  178. Tait SW, Oberst A, Quarato G, Milasta S, Haller M. 177.  et al. 2013. Widespread mitochondrial depletion via mitophagy does not compromise necroptosis. Cell Rep 5:878–85 [Google Scholar]
  179. Martins I, Wang Y, Michaud M, Ma Y, Sukkurwala AQ. 178.  et al. 2014. Molecular mechanisms of ATP secretion during immunogenic cell death. Cell Death Differ 21:79–91 [Google Scholar]
  180. Michaud M, Martins I, Sukkurwala AQ, Adjemian S, Ma Y. 179.  et al. 2011. Autophagy-dependent anticancer immune responses induced by chemotherapeutic agents in mice. Science 334:1573–77 [Google Scholar]
  181. Tang D, Kang R, Livesey KM, Cheh CW, Farkas A. 180.  et al. 2010. Endogenous HMGB1 regulates autophagy. J. Cell Biol. 190:881–92 [Google Scholar]
  182. Tang D, Kang R, Cheh CW, Livesey KM, Liang X. 181.  et al. 2010. HMGB1 release and redox regulates autophagy and apoptosis in cancer cells. Oncogene 29:5299–310 [Google Scholar]
  183. Martinez J, Almendinger J, Oberst A, Ness R, Dillon CP. 182.  et al. 2011. Microtubule-associated protein 1 light chain 3 alpha (LC3)-associated phagocytosis is required for the efficient clearance of dead cells. PNAS 108:17396–401 [Google Scholar]
  184. Brooks CR, Yeung MY, Brooks YS, Chen H, Ichimura T. 183.  et al. 2015. KIM-1-/TIM-1-mediated phagocytosis links ATG5-/ULK1-dependent clearance of apoptotic cells to antigen presentation. EMBO J 34:2441–64 [Google Scholar]
  185. Baghdadi M, Yoneda A, Yamashina T, Nagao H, Komohara Y. 184.  et al. 2013. TIM-4 glycoprotein-mediated degradation of dying tumor cells by autophagy leads to reduced antigen presentation and increased immune tolerance. Immunity 39:1070–81 [Google Scholar]
  186. Visvikis O, Ihuegbu N, Labed SA, Luhachack LG, Alves AM. 185.  et al. 2014. Innate host defense requires TFEB-mediated transcription of cytoprotective and antimicrobial genes. Immunity 40:896–909 [Google Scholar]
  187. Maurer K, Reyes-Robles T, Alonzo F, Durbin J, Torres VJ, Cadwell K. 186.  2015. Autophagy mediates tolerance to Staphylococcus aureus alpha-toxin. Cell Host Microbe 17:429–40 [Google Scholar]
  188. Figueiredo N, Chora A, Raquel H, Pejanovic N, Pereira P. 187.  et al. 2013. Anthracyclines induce DNA damage response-mediated protection against severe sepsis. Immunity 39:874–84 [Google Scholar]
  189. Marchiando AM, Ramanan D, Ding Y, Gomez LE, Hubbard-Lucey VM. 188.  et al. 2013. A deficiency in the autophagy gene Atg16L1 enhances resistance to enteric bacterial infection. Cell Host Microbe 14:216–24 [Google Scholar]
  190. Lu Q, Yokoyama CC, Williams JW, Baldridge MT, Jin XH. 189.  et al. 2016. Homeostatic control of innate lung inflammation by Vici syndrome gene Epg5 and additional autophagy genes promotes influenza pathogenesis. Cell Host Microbe 19:102–13 [Google Scholar]
  191. Park S, Buck MD, Desai C, Zhang X, Loginicheva E. 190.  et al. 2016. Autophagy genes enhance murine gammaherpesvirus 68 reactivation from latency by preventing virus-induced systemic inflammation. Cell Host Microbe 19:91–101 [Google Scholar]
  192. Murthy A, Li Y, Peng I, Reichelt M, Katakam AK. 191.  et al. 2014. A Crohn's disease variant in Atg16l1 enhances its degradation by caspase 3. Nature 506:456–62 [Google Scholar]
  193. Lassen KG, Kuballa P, Conway KL, Patel KK, Becker CE. 192.  et al. 2014. Atg16L1 T300A variant decreases selective autophagy resulting in altered cytokine signaling and decreased antibacterial defense. PNAS 111:7741–46 [Google Scholar]
  194. Gao P, Liu H, Huang H, Zhang Q, Strober W, Zhang F. 193.  2017. The inflammatory bowel disease-associated autophagy gene Atg16L1T300A acts as a dominant negative variant in mice. J. Immunol. 198:2457–67 [Google Scholar]
  195. Cabrera S, Fernandez AF, Marino G, Aguirre A, Suarez MF. 194.  et al. 2013. ATG4B/autophagin-1 regulates intestinal homeostasis and protects mice from experimental colitis. Autophagy 9:1188–200 [Google Scholar]
  196. Cadwell K, Patel KK, Komatsu M, Virgin HW 4th, Stappenbeck TS. 195.  2009. A common role for Atg16L1, Atg5 and Atg7 in small intestinal Paneth cells and Crohn disease. Autophagy 5:250–52 [Google Scholar]
  197. Adolph TE, Tomczak MF, Niederreiter L, Ko HJ, Bock J. 196.  et al. 2013. Paneth cells as a site of origin for intestinal inflammation. Nature 503:272–76 [Google Scholar]
  198. Cadwell K, Patel KK, Maloney NS, Liu TC, Ng AC. 197.  et al. 2010. Virus-plus-susceptibility gene interaction determines Crohn's disease gene Atg16L1 phenotypes in intestine. Cell 141:1135–45 [Google Scholar]
  199. Kernbauer E, Ding Y, Cadwell K. 198.  2014. An enteric virus can replace the beneficial function of commensal bacteria. Nature 516:94–98 [Google Scholar]
  200. Tschurtschenthaler M, Adolph TE, Ashcroft JW, Niederreiter L, Bharti R. 199.  et al. 2017. Defective ATG16L1-mediated removal of IRE1α drives Crohn's disease-like ileitis. J. Exp. Med. 214:401–22 [Google Scholar]
  201. Zhang H, Zheng L, McGovern DP, Hamill AM, Ichikawa R. 200.  et al. 2017. Myeloid ATG16L1 facilitates host-bacteria interactions in maintaining intestinal homeostasis. J. Immunol. 198:2133–46 [Google Scholar]
  202. Chu H, Khosravi A, Kusumawardhani IP, Kwon AH, Vasconcelos AC. 201.  et al. 2016. Gene-microbiota interactions contribute to the pathogenesis of inflammatory bowel disease. Science 352:1116–20 [Google Scholar]
  203. Kabat AM, Harrison OJ, Riffelmacher T, Moghaddam AE, Pearson CF. 202.  et al. 2016. The autophagy gene Atg16l1 differentially regulates Treg and TH2 cells to control intestinal inflammation. eLife 5:e12444 [Google Scholar]
  204. Schwerd T, Pandey S, Yang HT, Bagola K, Jameson E. 203.  et al. 2017. Impaired antibacterial autophagy links granulomatous intestinal inflammation in Niemann-Pick disease type C1 and XIAP deficiency with NOD2 variants in Crohn's disease. Gut 66:1060–73 [Google Scholar]
  205. de Luca A, Smeekens SP, Casagrande A, Iannitti R, Conway KL. 204.  et al. 2014. IL-1 receptor blockade restores autophagy and reduces inflammation in chronic granulomatous disease in mice and in humans. PNAS 111:3526–31 [Google Scholar]
  206. Xu K, Xu P, Yao JF, Zhang YG, Hou WK, Lu SM. 205.  2013. Reduced apoptosis correlates with enhanced autophagy in synovial tissues of rheumatoid arthritis. Inflamm. Res. 62:229–37 [Google Scholar]
  207. Kim EK, Kwon JE, Lee SY, Lee EJ, Kim DS. 206.  et al. 2017. IL-17-mediated mitochondrial dysfunction impairs apoptosis in rheumatoid arthritis synovial fibroblasts through activation of autophagy. Cell Death Dis 8:e2565 [Google Scholar]
  208. van Loosdregt J, Rossetti M, Spreafico R, Moshref M, Olmer M. 207.  et al. 2016. Increased autophagy in CD4+ T cells of rheumatoid arthritis patients results in T-cell hyperactivation and apoptosis resistance. Eur. J. Immunol. 46:2862–70 [Google Scholar]
  209. Lin NY, Beyer C, Giessl A, Kireva T, Scholtysek C. 208.  et al. 2013. Autophagy regulates TNFα-mediated joint destruction in experimental arthritis. Ann. Rheum. Dis. 72:761–68 [Google Scholar]
  210. Ireland JM, Unanue ER. 209.  2011. Autophagy in antigen-presenting cells results in presentation of citrullinated peptides to CD4 T cells. J. Exp. Med. 208:2625–32 [Google Scholar]
  211. Harley JB, Alarcon-Riquelme ME, Criswell LA, Jacob CO. 210. Int. Consort. Syst. Lupus Erythematosus Genet. et al. 2008. Genome-wide association scan in women with systemic lupus erythematosus identifies susceptibility variants in ITGAM, PXK, KIAA1542 and other loci. Nat. Genet. 40:204–10 [Google Scholar]
  212. Clarke AJ, Ellinghaus U, Cortini A, Stranks A, Simon AK. 211.  et al. 2015. Autophagy is activated in systemic lupus erythematosus and required for plasmablast development. Ann. Rheum. Dis. 74:912–20 [Google Scholar]
  213. Arnold J, Murera D, Arbogast F, Fauny JD, Muller S, Gros F. 212.  2016. Autophagy is dispensable for B-cell development but essential for humoral autoimmune responses. Cell Death Differ 23:853–64 [Google Scholar]
  214. Weindel CG, Richey LJ, Bolland S, Mehta AJ, Kearney JF, Huber BT. 213.  2015. B cell autophagy mediates TLR7-dependent autoimmunity and inflammation. Autophagy 11:1010–24 [Google Scholar]
  215. Weindel CG, Richey LJ, Mehta AJ, Shah M, Huber BT. 214.  2017. Autophagy in dendritic cells and B cells is critical for the inflammatory state of TLR7-mediated autoimmunity. J. Immunol. 198:1081–92 [Google Scholar]
  216. Henault J, Martinez J, Riggs JM, Tian J, Mehta P. 215.  et al. 2012. Noncanonical autophagy is required for type I interferon secretion in response to DNA-immune complexes. Immunity 37:986–97 [Google Scholar]
  217. Martinez J, Cunha LD, Park S, Yang M, Lu Q. 216.  et al. 2016. Noncanonical autophagy inhibits the autoinflammatory, lupus-like response to dying cells. Nature 533:115–19 [Google Scholar]
  218. Schuster C, Gerold KD, Schober K, Probst L, Boerner K. 217.  et al. 2015. The autoimmunity-associated gene CLEC16A modulates thymic epithelial cell autophagy and alters T cell selection. Immunity 42:942–52 [Google Scholar]
  219. Nedjic J, Aichinger M, Emmerich J, Mizushima N, Klein L. 218.  2008. Autophagy in thymic epithelium shapes the T-cell repertoire and is essential for tolerance. Nature 455:396–400 [Google Scholar]
  220. Soleimanpour SA, Gupta A, Bakay M, Ferrari AM, Groff DN. 219.  et al. 2014. The diabetes susceptibility gene Clec16a regulates mitophagy. Cell 157:1577–90 [Google Scholar]
  221. Redmann V, Lamb CA, Hwang S, Orchard RC, Kim S. 220.  et al. 2016. Clec16a is critical for autolysosome function and Purkinje cell survival. Sci. Rep. 6:23326 [Google Scholar]
  222. Qu X, Yu J, Bhagat G, Furuya N, Hibshoosh H. 221.  et al. 2003. Promotion of tumorigenesis by heterozygous disruption of the beclin 1 autophagy gene. J. Clin. Investig. 112:1809–20 [Google Scholar]
  223. Yue Z, Jin S, Yang C, Levine AJ, Heintz N. 222.  2003. Beclin 1, an autophagy gene essential for early embryonic development, is a haploinsufficient tumor suppressor. PNAS 100:15077–82 [Google Scholar]
  224. Takamura A, Komatsu M, Hara T, Sakamoto A, Kishi C. 223.  et al. 2011. Autophagy-deficient mice develop multiple liver tumors. Genes Dev 25:795–800 [Google Scholar]
  225. Rosenfeldt MT, O'Prey J, Morton JP, Nixon C, MacKay G. 224.  et al. 2013. p53 status determines the role of autophagy in pancreatic tumour development. Nature 504:296–300 [Google Scholar]
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