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Inflammatory Bowel Disease at the Intersection of Autophagy and Immunity: Insights from Human Genetics

  • Natalia B. Nedelsky
  • Petric Kuballa
  • Adam B. Castoreno
  • Ramnik J. Xavier
Chapter

Abstract

Studies using human genetics have identified more than 160 loci that affect the risk of developing inflammatory bowel disease (IBD), including Crohn’s disease (CD) and ulcerative colitis (UC). Several of these genes have been found to play key roles in the process of autophagy, a lysosome-based degradation pathway. Although historically considered to be a relatively nonselective process of degradation of cytosolic contents, autophagy has recently been revealed to have several selective and immune-specific functions that are relevant to the maintenance of intestinal homeostasis, including xenophagy, mitophagy, antigen presentation, secretion, and inflammasome regulation. In this chapter, we review the evidence that links autophagy-related genes, their immune-specific functions, and possible mechanisms of IBD pathogenesis. We summarize the basic molecular events underlying general and selective autophagy and present evidence suggesting possible pathogenic mechanisms revealed by studies of IBD-associated risk alleles of ATG16L1 and IRGM. Finally, we review chemical biology-based experimental approaches for identifying autophagy regulatory pathways that may have implications for the development of therapeutics.

Keywords

Inflammatory Bowel Disease Major Histocompatibility Complex Class Paneth Cell Vesicular Trafficking Autophagic Degradation 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Acknowledgments

This work was supported by funding from the Crohn’s and Colitis Foundation of America and NIH grants DK043351, DK083756, and DK086502 to R.J.X.

References

  1. 1.
    Mizushima N, Yoshimori T, Ohsumi Y (2011) The role of Atg proteins in autophagosome formation. Annu Rev Cell Dev Biol 27:107–132, Epub 2011/08/02PubMedCrossRefGoogle Scholar
  2. 2.
    Li W, Zou W, Yang Y, Chai Y, Chen B, Cheng S et al (2012) Autophagy genes function sequentially to promote apoptotic cell corpse degradation in the engulfing cell. J Cell Biol 197(1):27–35, Epub 2012/03/28PubMedCrossRefGoogle Scholar
  3. 3.
    Qu X, Zou Z, Sun Q, Luby-Phelps K, Cheng P, Hogan RN et al (2007) Autophagy gene-dependent clearance of apoptotic cells during embryonic development. Cell 128(5):931–946, Epub 2007/03/14PubMedCrossRefGoogle Scholar
  4. 4.
    Pierdominici M, Vomero M, Barbati C, Colasanti T, Maselli A, Vacirca D et al (2012) Role of autophagy in immunity and autoimmunity, with a special focus on systemic lupus erythematosus. FASEB J 26(4):1400–1412, Epub 2012/01/17PubMedCrossRefGoogle Scholar
  5. 5.
    Levine B, Mizushima N, Virgin HW (2011) Autophagy in immunity and inflammation. Nature 469(7330):323–335, Epub 2011/01/21PubMedCrossRefGoogle Scholar
  6. 6.
    Kuballa P, Nolte WM, Castoreno AB, Xavier RJ (2012) Autophagy and the immune system. Annu Rev Immunol 30:611–646, Epub 2012/03/28PubMedCrossRefGoogle Scholar
  7. 7.
    Deretic V (2011) Autophagy in immunity and cell-autonomous defense against intracellular microbes. Immunol Rev 240(1):92–104, Epub 2011/02/26PubMedCrossRefGoogle Scholar
  8. 8.
    Franke A, McGovern DP, Barrett JC, Wang K, Radford-Smith GL, Ahmad T et al (2010) Genome-wide meta-analysis increases to 71 the number of confirmed Crohn’s disease susceptibility loci. Nat Genet 42(12):1118–1125, Epub 2010/11/26PubMedCrossRefGoogle Scholar
  9. 9.
    Barrett JC, Hansoul S, Nicolae DL, Cho JH, Duerr RH, Rioux JD et al (2008) Genome-wide association defines more than 30 distinct susceptibility loci for Crohn’s disease. Nat Genet 40(8):955–962, Epub 2008/07/01PubMedCrossRefGoogle Scholar
  10. 10.
    Rioux JD, Xavier RJ, Taylor KD, Silverberg MS, Goyette P, Huett A et al (2007) Genome-wide association study identifies new susceptibility loci for Crohn disease and implicates autophagy in disease pathogenesis. Nat Genet 39(5):596–604, Epub 2007/04/17PubMedCrossRefGoogle Scholar
  11. 11.
    Hampe J, Franke A, Rosenstiel P, Till A, Teuber M, Huse K et al (2007) A genome-wide association scan of nonsynonymous SNPs identifies a susceptibility variant for Crohn disease in ATG16L1. Nat Genet 39(2):207–211, Epub 2007/01/04PubMedCrossRefGoogle Scholar
  12. 12.
    Anderson CA, Boucher G, Lees CW, Franke A, D’Amato M, Taylor KD et al (2011) Meta-analysis identifies 29 additional ulcerative colitis risk loci, increasing the number of confirmed associations to 47. Nat Genet 43(3):246–252, Epub 2011/02/08PubMedCrossRefGoogle Scholar
  13. 13.
    Jostins L, Ripke S, Weersma RK, Duerr RH, McGovern DP, Hui KY et al (2012) Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature 491(7422):119–124, Epub 2012/11/07PubMedCrossRefGoogle Scholar
  14. 14.
    Henckaerts L, Cleynen I, Brinar M, John JM, Van Steen K, Rutgeerts P et al (2011) Genetic variation in the autophagy gene ULK1 and risk of Crohn’s disease. Inflamm Bowel Dis 17(6):1392–1397, Epub 2011/05/12PubMedCrossRefGoogle Scholar
  15. 15.
    Brinar M, Vermeire S, Cleynen I, Lemmens B, Sagaert X, Henckaerts L et al (2012) Genetic variants in autophagy-related genes and granuloma formation in a cohort of surgically treated Crohn’s disease patients. J Crohns Colitis 6(1):43–50, Epub 2012/01/21PubMedCrossRefGoogle Scholar
  16. 16.
    Correia SC, Santos RX, Perry G, Zhu X, Moreira PI, Smith MA (2012) Mitochondrial importance in Alzheimer’s, Huntington’s and Parkinson’s diseases. Adv Exp Med Biol 724:205–221, Epub 2012/03/14PubMedCrossRefGoogle Scholar
  17. 17.
    Youle RJ, Narendra DP (2011) Mechanisms of mitophagy. Nat Rev Mol Cell Biol 12(1):9–14, Epub 2010/12/24PubMedCrossRefGoogle Scholar
  18. 18.
    Saitsu H, Nishimura T, Muramatsu K, Kodera H, Kumada S, Sugai K et al (2013) De novo mutations in the autophagy gene WDR45 cause static encephalopathy of childhood with neurodegeneration in adulthood. Nat Genet 45(4):445–449, Epub 2013/02/26PubMedCrossRefGoogle Scholar
  19. 19.
    Cullup T, Kho AL, Dionisi-Vici C, Brandmeier B, Smith F, Urry Z et al (2013) Recessive mutations in EPG5 cause Vici syndrome, a multisystem disorder with defective autophagy. Nat Genet 45(1):83–87, Epub 2012/12/12PubMedCrossRefGoogle Scholar
  20. 20.
    Inoue J, Nishiumi S, Fujishima Y, Masuda A, Shiomi H, Yamamoto K et al (2012) Autophagy in the intestinal epithelium regulates Citrobacter rodentium infection. Arch Biochem Biophys 521(1–2):95–101, Epub 2012/04/06PubMedCrossRefGoogle Scholar
  21. 21.
    Saitoh T, Fujita N, Jang MH, Uematsu S, Yang BG, Satoh T et al (2008) Loss of the autophagy protein Atg16L1 enhances endotoxin-induced IL-1beta production. Nature 456(7219):264–268, Epub 2008/10/14PubMedCrossRefGoogle Scholar
  22. 22.
    Travassos LH, Carneiro LA, Ramjeet M, Hussey S, Kim YG, Magalhaes JG et al (2010) Nod1 and Nod2 direct autophagy by recruiting ATG16L1 to the plasma membrane at the site of bacterial entry. Nat Immunol 11(1):55–62, Epub 2009/11/10PubMedCrossRefGoogle Scholar
  23. 23.
    Cooney R, Baker J, Brain O, Danis B, Pichulik T, Allan P et al (2010) NOD2 stimulation induces autophagy in dendritic cells influencing bacterial handling and antigen presentation. Nat Med 16(1):90–97, Epub 2009/12/08PubMedCrossRefGoogle Scholar
  24. 24.
    Tooze SA, Yoshimori T (2010) The origin of the autophagosomal membrane. Nat Cell Biol 12(9):831–835, Epub 2010/09/03PubMedCrossRefGoogle Scholar
  25. 25.
    Yang Z, Klionsky DJ (2010) Eaten alive: a history of macroautophagy. Nat Cell Biol 12(9):814–822, Epub 2010/09/03PubMedCrossRefGoogle Scholar
  26. 26.
    Tsukada M, Ohsumi Y (1993) Isolation and characterization of autophagy-defective mutants of Saccharomyces cerevisiae. FEBS Lett 333(1–2):169–174, Epub 1993/10/25PubMedCrossRefGoogle Scholar
  27. 27.
    Jung CH, Jun CB, Ro SH, Kim YM, Otto NM, Cao J et al (2009) ULK-Atg13-FIP200 complexes mediate mTOR signaling to the autophagy machinery. Mol Biol Cell 20(7):1992–2003, Epub 2009/02/20PubMedCrossRefGoogle Scholar
  28. 28.
    Kamada Y, Yoshino K, Kondo C, Kawamata T, Oshiro N, Yonezawa K et al (2010) Tor directly controls the Atg1 kinase complex to regulate autophagy. Mol Cell Biol 30(4):1049–1058, Epub 2009/12/10PubMedCrossRefGoogle Scholar
  29. 29.
    Cheong H, Nair U, Geng J, Klionsky DJ (2008) The Atg1 kinase complex is involved in the regulation of protein recruitment to initiate sequestering vesicle formation for nonspecific autophagy in Saccharomyces cerevisiae. Mol Biol Cell 19(2):668–681, Epub 2007/12/14PubMedCrossRefGoogle Scholar
  30. 30.
    Chan EY, Longatti A, McKnight NC, Tooze SA (2009) Kinase-inactivated ULK proteins inhibit autophagy via their conserved C-terminal domains using an Atg13-independent mechanism. Mol Cell Biol 29(1):157–171, Epub 2008/10/22PubMedCrossRefGoogle Scholar
  31. 31.
    Kageyama S, Omori H, Saitoh T, Sone T, Guan JL, Akira S et al (2011) The LC3 recruitment mechanism is separate from Atg9L1-dependent membrane formation in the autophagic response against Salmonella. Mol Biol Cell 22(13):2290–2300, Epub 2011/04/29PubMedCrossRefGoogle Scholar
  32. 32.
    Itakura E, Kishi C, Inoue K, Mizushima N (2008) Beclin 1 forms two distinct phosphatidylinositol 3-kinase complexes with mammalian Atg14 and UVRAG. Mol Biol Cell 19(12):5360–5372, Epub 2008/10/10PubMedCrossRefGoogle Scholar
  33. 33.
    Matsunaga K, Saitoh T, Tabata K, Omori H, Satoh T, Kurotori N et al (2009) Two Beclin 1-binding proteins, Atg14L and Rubicon, reciprocally regulate autophagy at different stages. Nat Cell Biol 11(4):385–396, Epub 2009/03/10PubMedCrossRefGoogle Scholar
  34. 34.
    Zhong Y, Wang QJ, Li X, Yan Y, Backer JM, Chait BT et al (2009) Distinct regulation of autophagic activity by Atg14L and Rubicon associated with Beclin 1-phosphatidylinositol-3-kinase complex. Nat Cell Biol 11(4):468–476, Epub 2009/03/10PubMedCrossRefGoogle Scholar
  35. 35.
    Sun Q, Fan W, Chen K, Ding X, Chen S, Zhong Q (2008) Identification of Barkor as a mammalian autophagy-specific factor for Beclin 1 and class III phosphatidylinositol 3-kinase. Proc Natl Acad Sci U S A 105(49):19211–19216, Epub 2008/12/04PubMedCrossRefGoogle Scholar
  36. 36.
    Matsunaga K, Morita E, Saitoh T, Akira S, Ktistakis NT, Izumi T et al (2010) Autophagy requires endoplasmic reticulum targeting of the PI3-kinase complex via Atg14L. J Cell Biol 190(4):511–521, Epub 2010/08/18PubMedCrossRefGoogle Scholar
  37. 37.
    Takahashi Y, Coppola D, Matsushita N, Cualing HD, Sun M, Sato Y et al (2007) Bif-1 interacts with Beclin 1 through UVRAG and regulates autophagy and tumorigenesis. Nat Cell Biol 9(10):1142–1151, Epub 2007/09/25PubMedCrossRefGoogle Scholar
  38. 38.
    Liang C, Feng P, Ku B, Dotan I, Canaani D, Oh BH et al (2006) Autophagic and tumour suppressor activity of a novel Beclin1-binding protein UVRAG. Nat Cell Biol 8(7):688–699, Epub 2006/06/27PubMedCrossRefGoogle Scholar
  39. 39.
    Liang C, Lee JS, Inn KS, Gack MU, Li Q, Roberts EA et al (2008) Beclin1-binding UVRAG targets the class C Vps complex to coordinate autophagosome maturation and endocytic trafficking. Nat Cell Biol 10(7):776–787, Epub 2008/06/17PubMedCrossRefGoogle Scholar
  40. 40.
    Mizushima N, Noda T, Yoshimori T, Tanaka Y, Ishii T, George MD et al (1998) A protein conjugation system essential for autophagy. Nature 395(6700):395–398, Epub 1998/10/06PubMedCrossRefGoogle Scholar
  41. 41.
    Mizushima N, Sugita H, Yoshimori T, Ohsumi Y (1998) A new protein conjugation system in human. The counterpart of the yeast Apg12p conjugation system essential for autophagy. J Biol Chem 273(51):33889–33892, Epub 1998/12/16PubMedCrossRefGoogle Scholar
  42. 42.
    Fujita N, Saitoh T, Kageyama S, Akira S, Noda T, Yoshimori T (2009) Differential involvement of Atg16L1 in Crohn disease and canonical autophagy: analysis of the organization of the Atg16L1 complex in fibroblasts. J Biol Chem 284(47):32602–32609, Epub 2009/09/29PubMedCrossRefGoogle Scholar
  43. 43.
    Noda NN, Ohsumi Y, Inagaki F (2010) Atg8-family interacting motif crucial for selective autophagy. FEBS Lett 584(7):1379–1385, Epub 2010/01/20PubMedCrossRefGoogle Scholar
  44. 44.
    Kabeya Y, Mizushima N, Ueno T, Yamamoto A, Kirisako T, Noda T et al (2000) LC3, a mammalian homologue of yeast Apg8p, is localized in autophagosome membranes after processing. EMBO J 19(21):5720–5728, Epub 2000/11/04PubMedCrossRefGoogle Scholar
  45. 45.
    Kabeya Y, Mizushima N, Yamamoto A, Oshitani-Okamoto S, Ohsumi Y, Yoshimori T (2004) LC3, GABARAP and GATE16 localize to autophagosomal membrane depending on form-II formation. J Cell Sci 117(pt 13):2805–2812, Epub 2004/06/01PubMedCrossRefGoogle Scholar
  46. 46.
    Satoo K, Noda NN, Kumeta H, Fujioka Y, Mizushima N, Ohsumi Y et al (2009) The structure of Atg4B-LC3 complex reveals the mechanism of LC3 processing and delipidation during autophagy. EMBO J 28(9):1341–1350, Epub 2009/03/27PubMedCrossRefGoogle Scholar
  47. 47.
    Weidberg H, Shvets E, Shpilka T, Shimron F, Shinder V, Elazar Z (2010) LC3 and GATE-16/GABARAP subfamilies are both essential yet act differently in autophagosome biogenesis. EMBO J 29(11):1792–1802, Epub 2010/04/27PubMedCrossRefGoogle Scholar
  48. 48.
    Kimura S, Noda T, Yoshimori T (2008) Dynein-dependent movement of autophagosomes mediates efficient encounters with lysosomes. Cell Struct Funct 33(1):109–122, Epub 2008/04/05PubMedCrossRefGoogle Scholar
  49. 49.
    Korolchuk VI, Saiki S, Lichtenberg M, Siddiqi FH, Roberts EA, Imarisio S et al (2011) Lysosomal positioning coordinates cellular nutrient responses. Nat Cell Biol 13(4):453–460, Epub 2011/03/12PubMedCrossRefGoogle Scholar
  50. 50.
    Lavoie JN, Hickey E, Weber LA, Landry J (1993) Modulation of actin microfilament dynamics and fluid phase pinocytosis by phosphorylation of heat shock protein 27. J Biol Chem 268(32):24210–24214, Epub 1993/11/15PubMedGoogle Scholar
  51. 51.
    Tang D, Kang R, Livesey KM, Kroemer G, Billiar TR, Van Houten B et al (2011) High-mobility group box 1 is essential for mitochondrial quality control. Cell Metab 13(6):701–711, Epub 2011/06/07PubMedCrossRefGoogle Scholar
  52. 52.
    Settembre C, Di Malta C, Polito VA, Garcia Arencibia M, Vetrini F, Erdin S et al (2011) TFEB links autophagy to lysosomal biogenesis. Science 332(6036):1429–1433, Epub 2011/05/28PubMedCrossRefGoogle Scholar
  53. 53.
    Yu XJ, McGourty K, Liu M, Unsworth KE, Holden DW (2010) pH sensing by intracellular Salmonella induces effector translocation. Science 328(5981):1040–1043, Epub 2010/04/17PubMedCrossRefGoogle Scholar
  54. 54.
    Patel JC, Hueffer K, Lam TT, Galan JE (2009) Diversification of a Salmonella virulence protein function by ubiquitin-dependent differential localization. Cell 137(2):283–294, Epub 2009/04/22PubMedCrossRefGoogle Scholar
  55. 55.
    Bakowski MA, Braun V, Lam GY, Yeung T, Heo WD, Meyer T et al (2010) The phosphoinositide phosphatase SopB manipulates membrane surface charge and trafficking of the Salmonella-containing vacuole. Cell Host Microbe 7(6):453–462, Epub 2010/06/15PubMedCrossRefGoogle Scholar
  56. 56.
    Zheng YT, Shahnazari S, Brech A, Lamark T, Johansen T, Brumell JH (2009) The adaptor protein p62/SQSTM1 targets invading bacteria to the autophagy pathway. J Immunol 183(9):5909–5916, Epub 2009/10/09PubMedCrossRefGoogle Scholar
  57. 57.
    Thurston TL, Ryzhakov G, Bloor S, von Muhlinen N, Randow F (2009) The TBK1 adaptor and autophagy receptor NDP52 restricts the proliferation of ubiquitin-coated bacteria. Nat Immunol 10(11):1215–1221, Epub 2009/10/13PubMedCrossRefGoogle Scholar
  58. 58.
    Korioth F, Gieffers C, Maul GG, Frey J (1995) Molecular characterization of NDP52, a novel protein of the nuclear domain 10, which is redistributed upon virus infection and interferon treatment. J Cell Biol 130(1):1–13, Epub 1995/07/01PubMedCrossRefGoogle Scholar
  59. 59.
    Sternsdorf T, Jensen K, Zuchner D, Will H (1997) Cellular localization, expression, and structure of the nuclear dot protein 52. J Cell Biol 138(2):435–448, Epub 1997/07/28PubMedCrossRefGoogle Scholar
  60. 60.
    Cemma M, Kim PK, Brumell JH (2011) The ubiquitin-binding adaptor proteins p62/SQSTM1 and NDP52 are recruited independently to bacteria-associated microdomains to target Salmonella to the autophagy pathway. Autophagy 7(3):341–345, Epub 2010/11/17PubMedCrossRefGoogle Scholar
  61. 61.
    Mostowy S, Sancho-Shimizu V, Hamon M, Simeone R, Brosch R, Johansen T et al (2011) p62 and NDP52 target intracytosolic Shigella and Listeria to different autophagy pathways. J Biol Chem 286(30):26987–26995, Epub 2011/06/08PubMedCrossRefGoogle Scholar
  62. 62.
    Veiga E, Cossart P (2005) Ubiquitination of intracellular bacteria: a new bacteria-sensing system? Trends Cell Biol 15(1):2–5, Epub 2005/01/18PubMedCrossRefGoogle Scholar
  63. 63.
    Birmingham CL, Smith AC, Bakowski MA, Yoshimori T, Brumell JH (2006) Autophagy controls Salmonella infection in response to damage to the Salmonella-containing vacuole. J Biol Chem 281(16):11374–11383, Epub 2006/02/24PubMedCrossRefGoogle Scholar
  64. 64.
    Huett A, Heath RJ, Begun J, Sassi SO, Baxt LA, Vyas JM 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(6):778–790, Epub 2012/12/19PubMedCrossRefGoogle Scholar
  65. 65.
    Reis BS, Mucida D (2012) The role of the intestinal context in the generation of tolerance and inflammation. Clin Dev Immunol 2012:157948, Epub 2011/09/29PubMedCrossRefGoogle Scholar
  66. 66.
    Lapaquette P, Glasser AL, Huett A, Xavier RJ, Darfeuille-Michaud A (2010) Crohn’s disease-associated adherent-invasive E. coli are selectively favoured by impaired autophagy to replicate intracellularly. Cell Microbiol 12(1):99–113, Epub 2009/09/15PubMedCrossRefGoogle Scholar
  67. 67.
    Kuballa P, Huett A, Rioux JD, Daly MJ, Xavier RJ (2008) Impaired autophagy of an intracellular pathogen induced by a Crohn’s disease associated ATG16L1 variant. PLoS One 3(10):e3391, Epub 2008/10/15PubMedCrossRefGoogle Scholar
  68. 68.
    McCarroll SA, Huett A, Kuballa P, Chilewski SD, Landry A, Goyette P et al (2008) Deletion polymorphism upstream of IRGM associated with altered IRGM expression and Crohn’s disease. Nat Genet 40(9):1107–1112, Epub 2009/01/24PubMedCrossRefGoogle Scholar
  69. 69.
    Brest P, Lapaquette P, Souidi M, Lebrigand K, Cesaro A, Vouret-Craviari V et al (2011) A synonymous variant in IRGM alters a binding site for miR-196 and causes deregulation of IRGM-dependent xenophagy in Crohn’s disease. Nat Genet 43(3):242–245, Epub 2011/02/01PubMedCrossRefGoogle Scholar
  70. 70.
    Tong Y, Giaime E, Yamaguchi H, Ichimura T, Liu Y, Si H et al (2012) Loss of leucine-rich repeat kinase 2 causes age-dependent bi-phasic alterations of the autophagy pathway. Mol Neurodegener 7:2, Epub 2012/01/11PubMedCrossRefGoogle Scholar
  71. 71.
    Plowey ED, Cherra SJ III, Liu YJ, Chu CT (2008) Role of autophagy in G2019S-LRRK2-associated neurite shortening in differentiated SH-SY5Y cells. J Neurochem 105(3):1048–1056, Epub 2008/01/10PubMedCrossRefGoogle Scholar
  72. 72.
    Gardet A, Benita Y, Li C, Sands BE, Ballester I, Stevens C et al (2010) LRRK2 is involved in the IFN-gamma response and host response to pathogens. J Immunol 185(9):5577–5585, Epub 2010/10/06PubMedCrossRefGoogle Scholar
  73. 73.
    Kumar D, Nath L, Kamal MA, Varshney A, Jain A, Singh S et al (2010) Genome-wide analysis of the host intracellular network that regulates survival of Mycobacterium tuberculosis. Cell 140(5):731–743, Epub 2010/03/10PubMedCrossRefGoogle Scholar
  74. 74.
    Intemann CD, Thye T, Niemann S, Browne EN, Amanua Chinbuah M, Enimil A et al (2009) Autophagy gene variant IRGM -261T contributes to protection from tuberculosis caused by Mycobacterium tuberculosis but not by M. africanum strains. PLoS Pathog 5(9):e1000577, Epub 2009/09/15PubMedCrossRefGoogle Scholar
  75. 75.
    Chiodini RJ, Chamberlin WM, Sarosiek J, McCallum RW (2012) Crohn’s disease and the mycobacterioses: a quarter century later. Causation or simple association? Crit Rev Microbiol 38(1):52–93, Epub 2012/01/17PubMedCrossRefGoogle Scholar
  76. 76.
    Orvedahl A, Sumpter R Jr, Xiao G, Ng A, Zou Z, Tang Y et al (2011) Image-based genome-wide siRNA screen identifies selective autophagy factors. Nature 480(7375):113–117, Epub 2011/10/25PubMedCrossRefGoogle Scholar
  77. 77.
    Matsuda N, Sato S, Shiba K, Okatsu K, Saisho K, Gautier CA et al (2010) PINK1 stabilized by mitochondrial depolarization recruits Parkin to damaged mitochondria and activates latent Parkin for mitophagy. J Cell Biol 189(2):211–221, Epub 2010/04/21PubMedCrossRefGoogle Scholar
  78. 78.
    Narendra D, Kane LA, Hauser DN, Fearnley IM, Youle RJ (2010) p62/SQSTM1 is required for Parkin-induced mitochondrial clustering but not mitophagy; VDAC1 is dispensable for both. Autophagy 6(8):1090–1106, Epub 2010/10/05PubMedCrossRefGoogle Scholar
  79. 79.
    Jin SM, Lazarou M, Wang C, Kane LA, Narendra DP, Youle RJ (2010) Mitochondrial membrane potential regulates PINK1 import and proteolytic destabilization by PARL. J Cell Biol 191(5):933–942, Epub 2010/12/01PubMedCrossRefGoogle Scholar
  80. 80.
    Geisler S, Holmstrom KM, Skujat D, Fiesel FC, Rothfuss OC, Kahle PJ et al (2010) PINK1/Parkin-mediated mitophagy is dependent on VDAC1 and p62/SQSTM1. Nat Cell Biol 12(2):119–131, Epub 2010/01/26PubMedCrossRefGoogle Scholar
  81. 81.
    Tanaka A, Cleland MM, Xu S, Narendra DP, Suen DF, Karbowski M et al (2010) Proteasome and p97 mediate mitophagy and degradation of mitofusins induced by Parkin. J Cell Biol 191(7):1367–1380, Epub 2010/12/22PubMedCrossRefGoogle Scholar
  82. 82.
    Gegg ME, Cooper JM, Chau KY, Rojo M, Schapira AH, Taanman JW (2010) Mitofusin 1 and mitofusin 2 are ubiquitinated in a PINK1/parkin-dependent manner upon induction of mitophagy. Hum Mol Genet 19(24):4861–4870, Epub 2010/09/28PubMedCrossRefGoogle Scholar
  83. 83.
    Ziviani E, Tao RN, Whitworth AJ (2010) Drosophila parkin requires PINK1 for mitochondrial translocation and ubiquitinates mitofusin. Proc Natl Acad Sci U S A 107(11):5018–5023, Epub 2010/03/03PubMedCrossRefGoogle Scholar
  84. 84.
    Fimia GM, Stoykova A, Romagnoli A, Giunta L, Di Bartolomeo S, Nardacci R et al (2007) Ambra1 regulates autophagy and development of the nervous system. Nature 447(7148):1121–1125, Epub 2007/06/26PubMedGoogle Scholar
  85. 85.
    Van Humbeeck C, Cornelissen T, Hofkens H, Mandemakers W, Gevaert K, De Strooper B et al (2011) Parkin interacts with ambra1 to induce mitophagy. J Neurosci 31(28):10249–10261, Epub 2011/07/15PubMedCrossRefGoogle Scholar
  86. 86.
    Dengjel J, Schoor O, Fischer R, Reich M, Kraus M, Muller M et al (2005) Autophagy promotes MHC class II presentation of peptides from intracellular source proteins. Proc Natl Acad Sci U S A 102(22):7922–7927, Epub 2005/05/17PubMedCrossRefGoogle Scholar
  87. 87.
    Kasai M, Tanida I, Ueno T, Kominami E, Seki S, Ikeda T et al (2009) Autophagic compartments gain access to the MHC class II compartments in thymic epithelium. J Immunol 183(11):7278–7285, Epub 2009/11/17PubMedCrossRefGoogle Scholar
  88. 88.
    Schmid D, Pypaert M, Munz C (2007) Antigen-loading compartments for major histocompatibility complex class II molecules continuously receive input from autophagosomes. Immunity 26(1):79–92, Epub 2006/12/22PubMedCrossRefGoogle Scholar
  89. 89.
    Lee HK, Mattei LM, Steinberg BE, Alberts P, Lee YH, Chervonsky A et al (2010) In vivo requirement for Atg5 in antigen presentation by dendritic cells. Immunity 32(2):227–239, Epub 2010/02/23PubMedCrossRefGoogle Scholar
  90. 90.
    Ireland JM, Unanue ER (2011) Autophagy in antigen-presenting cells results in presentation of citrullinated peptides to CD4 T cells. J Exp Med 208(13):2625–2632, Epub 2011/12/14PubMedCrossRefGoogle Scholar
  91. 91.
    Paludan C, Schmid D, Landthaler M, Vockerodt M, Kube D, Tuschl T et al (2005) Endogenous MHC class II processing of a viral nuclear antigen after autophagy. Science 307(5709):593–596, Epub 2004/12/14PubMedCrossRefGoogle Scholar
  92. 92.
    Wildenberg ME, Vos AC, Wolfkamp SC, Duijvestein M, Verhaar AP, Te Velde AA et al (2012) Autophagy attenuates the adaptive immune response by destabilizing the immunologic synapse. Gastroenterology 142(7):1493–503.e6, Epub 2012/03/01PubMedCrossRefGoogle Scholar
  93. 93.
    Bevins CL, Salzman NH (2011) Paneth cells, antimicrobial peptides and maintenance of intestinal homeostasis. Nat Rev Microbiol 9(5):356–368, Epub 2011/03/23PubMedCrossRefGoogle Scholar
  94. 94.
    Cadwell K, Patel KK, Maloney NS, Liu TC, Ng AC, Storer CE et al (2010) Virus-plus-susceptibility gene interaction determines Crohn’s disease gene Atg16L1 phenotypes in intestine. Cell 141(7):1135–1145, Epub 2010/07/07PubMedCrossRefGoogle Scholar
  95. 95.
    Cadwell K, Liu JY, Brown SL, Miyoshi H, Loh J, Lennerz JK et al (2008) A key role for autophagy and the autophagy gene Atg16l1 in mouse and human intestinal Paneth cells. Nature 456(7219):259–262PubMedCrossRefGoogle Scholar
  96. 96.
    Cadwell K, Patel KK, Komatsu M, Virgin HW, Stappenbeck TS (2009) A common role for Atg16L1, Atg5 and Atg7 in small intestinal Paneth cells and Crohn disease. Autophagy 5(2):250–252PubMedCrossRefGoogle Scholar
  97. 97.
    Biswas A, Liu YJ, Hao L, Mizoguchi A, Salzman NH, Bevins CL et al (2010) Induction and rescue of Nod2-dependent Th1-driven granulomatous inflammation of the ileum. Proc Natl Acad Sci U S A 107(33):14739–14744, Epub 2010/08/04PubMedCrossRefGoogle Scholar
  98. 98.
    Kaser A, Lee AH, Franke A, Glickman JN, Zeissig S, Tilg H et al (2008) XBP1 links ER stress to intestinal inflammation and confers genetic risk for human inflammatory bowel disease. Cell 134(5):743–756, Epub 2008/09/09PubMedCrossRefGoogle Scholar
  99. 99.
    Yilmaz OH, Katajisto P, Lamming DW, Gultekin Y, Bauer-Rowe KE, Sengupta S et al (2012) mTORC1 in the Paneth cell niche couples intestinal stem-cell function to calorie intake. Nature 486(7404):490–495, Epub 2012/06/23PubMedGoogle Scholar
  100. 100.
    Zhou R, Yazdi AS, Menu P, Tschopp J (2011) A role for mitochondria in NLRP3 inflammasome activation. Nature 469(7329):221–225, Epub 2010/12/03PubMedCrossRefGoogle Scholar
  101. 101.
    Bulua AC, Simon A, Maddipati R, Pelletier M, Park H, Kim KY et al (2011) Mitochondrial reactive oxygen species promote production of proinflammatory cytokines and are elevated in TNFR1-associated periodic syndrome (TRAPS). J Exp Med 208(3):519–533, Epub 2011/02/02PubMedCrossRefGoogle Scholar
  102. 102.
    Wen H, Gris D, Lei Y, Jha S, Zhang L, Huang MT et al (2011) Fatty acid-induced NLRP3-ASC inflammasome activation interferes with insulin signaling. Nat Immunol 12(5):408–415, Epub 2011/04/12PubMedCrossRefGoogle Scholar
  103. 103.
    Plantinga TS, Crisan TO, Oosting M, van de Veerdonk FL, de Jong DJ, Philpott DJ et al (2011) Crohn’s disease-associated ATG16L1 polymorphism modulates pro-inflammatory cytokine responses selectively upon activation of NOD2. Gut 60(9):1229–1235, Epub 2011/03/17PubMedCrossRefGoogle Scholar
  104. 104.
    Lee J, Kim HR, Quinley C, Kim J, Gonzalez-Navajas J, Xavier R et al (2012) Autophagy suppresses interleukin-1beta (IL-1beta) signaling by activation of p62 degradation via lysosomal and proteasomal pathways. J Biol Chem 287(6):4033–4040, Epub 2011/12/15PubMedCrossRefGoogle Scholar
  105. 105.
    Raju D, Hussey S, Ang M, Terebiznik MR, Sibony M, Galindo-Mata E et al (2012) Vacuolating cytotoxin and variants in Atg16L1 that disrupt autophagy promote Helicobacter pylori infection in humans. Gastroenterology 142(5):1160–1171, Epub 2012/02/16PubMedCrossRefGoogle Scholar
  106. 106.
    Singh SB, Ornatowski W, Vergne I, Naylor J, Delgado M, Roberts E et al (2010) Human IRGM regulates autophagy and cell-autonomous immunity functions through mitochondria. Nat Cell Biol 12(12):1154–1165, Epub 2010/11/26PubMedCrossRefGoogle Scholar
  107. 107.
    Parkes M, Barrett JC, Prescott NJ, Tremelling M, Anderson CA, Fisher SA et al (2007) Sequence variants in the autophagy gene IRGM and multiple other replicating loci contribute to Crohn’s disease susceptibility. Nat Genet 39(7):830–832, Epub 2007/06/08PubMedCrossRefGoogle Scholar
  108. 108.
    Behrends C, Sowa ME, Gygi SP, Harper JW (2010) Network organization of the human autophagy system. Nature 466(7302):68–76, Epub 2010/06/22PubMedCrossRefGoogle Scholar
  109. 109.
    Rozenknop A, Rogov VV, Rogova NY, Lohr F, Guntert P, Dikic I et al (2011) Characterization of the Interaction of GABARAPL-1 with the LIR Motif of NBR1. J Mol Biol 410(3):477–487, Epub 2011/05/31PubMedCrossRefGoogle Scholar
  110. 110.
    Kraft C, Peter M, Hofmann K (2010) Selective autophagy: ubiquitin-mediated recognition and beyond. Nat Cell Biol 12(9):836–841, Epub 2010/09/03PubMedCrossRefGoogle Scholar
  111. 111.
    Ong SE, Schenone M, Margolin AA, Li X, Do K, Doud MK et al (2009) Identifying the proteins to which small-molecule probes and drugs bind in cells. Proc Natl Acad Sci U S A 106(12):4617–4622, Epub 2009/03/04PubMedCrossRefGoogle Scholar
  112. 112.
    Lamb J, Crawford ED, Peck D, Modell JW, Blat IC, Wrobel MJ et al (2006) The Connectivity Map: using gene-expression signatures to connect small molecules, genes, and disease. Science 313(5795):1929–1935, Epub 2006/09/30PubMedCrossRefGoogle Scholar
  113. 113.
    Zhang L, Yu J, Pan H, Hu P, Hao Y, Cai W et al (2007) Small molecule regulators of autophagy identified by an image-based high-throughput screen. Proc Natl Acad Sci U S A 104(48):19023–19028, Epub 2007/11/21PubMedCrossRefGoogle Scholar
  114. 114.
    Balgi AD, Fonseca BD, Donohue E, Tsang TC, Lajoie P, Proud CG et al (2009) Screen for chemical modulators of autophagy reveals novel therapeutic inhibitors of mTORC1 signaling. PLoS One 4(9):e7124, Epub 2009/09/23PubMedCrossRefGoogle Scholar
  115. 115.
    Sarkar S, Perlstein EO, Imarisio S, Pineau S, Cordenier A, Maglathlin RL et al (2007) Small molecules enhance autophagy and reduce toxicity in Huntington’s disease models. Nat Chem Biol 3(6):331–338, Epub 2007/05/09PubMedCrossRefGoogle Scholar
  116. 116.
    Farkas T, Hoyer-Hansen M, Jaattela M (2009) Identification of novel autophagy regulators by a luciferase-based assay for the kinetics of autophagic flux. Autophagy 5(7):1018–1025, Epub 2009/08/05PubMedCrossRefGoogle Scholar
  117. 117.
    Fleming A, Noda T, Yoshimori T, Rubinsztein DC (2011) Chemical modulators of autophagy as biological probes and potential therapeutics. Nat Chem Biol 7(1):9–17, Epub 2010/12/18PubMedCrossRefGoogle Scholar
  118. 118.
    Sarkar S, Korolchuk VI, Renna M, Imarisio S, Fleming A, Williams A et al (2011) Complex inhibitory effects of nitric oxide on autophagy. Mol Cell 43(1):19–32, Epub 2011/07/06PubMedCrossRefGoogle Scholar
  119. 119.
    Kang R, Livesey KM, Zeh HJ 3rd, Loze MT, Tang D (2011) Metabolic regulation by HMGB1-mediated autophagy and mitophagy. Autophagy 7(10):1256–1258, Epub 2011/06/22PubMedCrossRefGoogle Scholar
  120. 120.
    Chen G, Xia H, Cai Y, Ma D, Yuan J, Yuan C (2011) Synthesis and SAR study of diphenylbutylpiperidines as cell autophagy inducers. Bioorg Med Chem Lett 21(1):234–239, Epub 2010/12/04PubMedCrossRefGoogle Scholar
  121. 121.
    Chou TF, Brown SJ, Minond D, Nordin BE, Li K, Jones AC et al (2011) Reversible inhibitor of p97, DBeQ, impairs both ubiquitin-dependent and autophagic protein clearance pathways. Proc Natl Acad Sci U S A 108(12):4834–4839, Epub 2011/03/09PubMedCrossRefGoogle Scholar
  122. 122.
    Miller S, Tavshanjian B, Oleksy A, Perisic O, Houseman BT, Shokat KM et al (2010) Shaping development of autophagy inhibitors with the structure of the lipid kinase Vps34. Science 327(5973):1638–1642, Epub 2010/03/27PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Natalia B. Nedelsky
    • 1
  • Petric Kuballa
    • 1
    • 2
  • Adam B. Castoreno
    • 1
    • 2
  • Ramnik J. Xavier
    • 1
    • 2
  1. 1.Gastrointestinal UnitCenter for the Study of Inflammatory Bowel Disease, and Center for Computational and Integrative Biology, Massachusetts General HospitalBostonUSA
  2. 2.Broad Institute of Harvard University and Massachusetts Institute of TechnologyCambridgeUSA

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