Defective ATG16L1-mediated removal of IRE1α drives Crohn's disease-like ileitis

Journal of Experimental Medicine

Volumn 214, Issue 2, 2017, Pages 401-422

  Tschurtschenthaler, Markus ^a   Adolph, Timon E ^a   Ashcroft, Jonathan W ^a   Niederreiter, Lukas ^a   Bharti, Richa ^c   Saveljeva, Svetlana ^a   Bhattacharyya, Joya ^a   Flak, Magdalena B ^d   Shih, David Q ^e   Fuhler, Gwenny M ^f   Parkes, Miles ^a   Kohno, Kenji ^g   Iwawaki, Takao ^h   van der Woude, C Janneke ^f   Harding, Heather P ^b   Smith, Andrew M ⁱ   Peppelenbosch, Maikel P ^f   Targan, Stephan R ^e   Ron, David ^b   Rosenstiel, Philip ^c   Blumberg, Richard S ^d   Kaser, Arthur ^a   more..

^a UNIVERSITY OF CAMBRIDGE   (United Kingdom)

^b UNIVERSITY OF CAMBRIDGE   (United Kingdom)

^c UNIVERSITY OF KIEL   (Germany)

^d BRIGHAM AND WOMEN S HOSPITAL   (United States)

^e CEDARS SINAI MEDICAL CENTER   (United States)

^f ERASMUS MEDICAL CENTER   (Netherlands)

^g NARA INSTITUTE OF SCIENCE AND TECHNOLOGY   (Japan)

^h KANAZAWA MEDICAL UNIVERSITY   (Japan)

ⁱ UNIVERSITY COLLEGE LONDON   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

OPTINEURIN; PROTEIN IRE1; X BOX BINDING PROTEIN 1; ATG16L1 PROTEIN, HUMAN; AUTOPHAGY RELATED PROTEIN; ERN1 PROTEIN, MOUSE; ERN2 PROTEIN, MOUSE; MEMBRANE PROTEIN; PROTEIN SERINE THREONINE KINASE; RIBONUCLEASE;

AGING; ANIMAL CELL; ANIMAL CELL CULTURE; ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ARTICLE; ATG16L1 GENE; CROHN DISEASE; DYSBIOSIS; ENDOPLASMIC RETICULUM STRESS; GENE; GENE DELETION; HISTOLOGY; HUMAN; HUMAN TISSUE; ILEITIS; IMMUNOREACTIVITY; INTESTINE BIOPSY; INTESTINE EPITHELIUM CELL; INTESTINE FLORA; MOUSE; NONHUMAN; PANETH CELL; PRIORITY JOURNAL; RIBOTYPING; SELECTIVE AUTOPHAGY; UNFOLDED PROTEIN RESPONSE; AGE; ANIMAL; AUTOPHAGY; C57BL MOUSE; MICROFLORA; PHYSIOLOGY;

AGE FACTORS; ANIMALS; AUTOPHAGY; AUTOPHAGY-RELATED PROTEINS; CROHN DISEASE; ENDOPLASMIC RETICULUM STRESS; ENDORIBONUCLEASES; ILEITIS; MEMBRANE PROTEINS; MICE; MICE, INBRED C57BL; MICROBIOTA; PROTEIN-SERINE-THREONINE KINASES;

EID: 85012261819     PISSN: 00221007     EISSN: 15409538     Source Type: Journal    
DOI: 10.1084/jem.20160791     Document Type: Article

References (91)

1. Adolph, T.E., M.F. Tomczak, L. Niederreiter, H.J. Ko, J. Böck, E. Martinez-Naves, J.N. Glickman, M. Tschurtschenthaler, J. Hartwig, S. Hosomi, et al. 2013. Paneth cells as a site of origin for intestinal inflammation. Nature. 503:272-276.
2. Amthor, H., A. Otto, A. Vulin, A. Rochat, J. Dumonceaux, L. Garcia, E. Mouisel, C. Hourdé, R. Macharia, M. Friedrichs, et al. 2009. Muscle hypertrophy driven by myostatin blockade does not require stem/precursor-cell activity. Proc. Natl. Acad. Sci. USA. 106:7479-7484. http://dx.doi.org/10.1073/pnas.0811129106
3. Anderson, M.J. 2001. A new method for non-parametric multivariate analysis of variance. Austral Ecol. 26:32-46.
4. Baxt, L.A., and R.J. Xavier. 2015. Role of autophagy in the maintenance of intestinal homeostasis. Gastroenterology. 149:553-562. http://dx.doi.org/10.1053/j.gastro.2015.06.046
5. Bertolotti, A., X. Wang, I. Novoa, R. Jungreis, K. Schlessinger, J.H. Cho, A.B. West, and D. Ron. 2001. Increased sensitivity to dextran sodium sulfate colitis in IRE1β-deficient mice. J. Clin. Invest. 107:585-593. http://dx.doi.org/10.1172/JCI11476
6. Biswas, A., Y.J. Liu, L. Hao, A. Mizoguchi, N.H. Salzman, C.L. Bevins, and K.S. Kobayashi. 2010. Induction and rescue of Nod2-dependent Th1-driven granulomatous inflammation of the ileum. Proc. Natl. Acad. Sci. USA. 107:14739-14744. http://dx.doi.org/10.1073/pnas.1003363107
7. Cadwell, K., J.Y. Liu, S.L. Brown, H. Miyoshi, J. Loh, J.K. Lennerz, C. Kishi, W. Kc, J.A. Carrero, S. Hunt, et al. 2008. A key role for autophagy and the autophagy gene Atg16l1 in mouse and human intestinal Paneth cells. Nature. 456:259-263. http://dx.doi.org/10.1038/nature07416
8. Cadwell, K., K.K. Patel, N.S. Maloney, T.C. Liu, A.C. Ng, C.E. Storer, R.D. Head, R. Xavier, T.S. Stappenbeck, and H.W. Virgin. 2010. Virus-plussusceptibility gene interaction determines Crohn's disease gene Atg16L1 phenotypes in intestine. Cell. 141:1135-1145. http://dx.doi.org/10.1016/j.cell.2010.05.009
9. Chen, Y., and F. Brandizzi. 2013. IRE1: ER stress sensor and cell fate executor. Trends Cell Biol. 23:547-555. http://dx.doi.org/10.1016/j.tcb.2013.06.005
10. Chew, T.S., N.R. O'Shea, G.W. Sewell, S.H. Oehlers, C.M. Mulvey, P.S. Crosier, J. Godovac-Zimmermann, S.L. Bloom, A.M. Smith, and A.W. Segal. 2015. Optineurin deficiency in mice contributes to impaired cytokine secretion and neutrophil recruitment in bacteria-driven colitis. Dis. Model. Mech. 8:817-829. http://dx.doi.org/10.1242/dmm.020362
11. Cho, J.A., A.H. Lee, B. Platzer, B.C. Cross, B.M. Gardner, H. De Luca, P. Luong, H.P. Harding, L.H. Glimcher, P. Walter, et al. 2013. The unfolded protein response element IRE1α senses bacterial proteins invading the ER to activate RIG-I and innate immune signaling. Cell Host Microbe. 13:558-569. http://dx.doi.org/10.1016/j.chom.2013.03.011
12. Clevers, H.C., and C.L. Bevins. 2013. Paneth cells: maestros of the small intestinal crypts. Annu. Rev. Physiol. 75:289-311. http://dx.doi.org/10.1146/annurev-physiol-030212-183744
13. Conway, K.L., P. Kuballa, J.H. Song, K.K. Patel, A.B. Castoreno, O.H. Yilmaz, H.B. Jijon, M. Zhang, L.N. Aldrich, E.J. Villablanca, et al. 2013. Atg16l1 is required for autophagy in intestinal epithelial cells and protection of mice from Salmonella infection. Gastroenterology. 145:1347-1357. http://dx.doi.org/10.1053/j.gastro.2013.08.035
14. Cooney, R., J. Baker, O. Brain, B. Danis, T. Pichulik, P. Allan, D.J. Ferguson, B.J. Campbell, D. Jewell, and A. Simmons. 2010. NOD2 stimulation induces autophagy in dendritic cells influencing bacterial handling and antigen presentation. Nat. Med. 16:90-97. http://dx.doi.org/10.1038/nm.2069
15. Couturier-Maillard, A., T. Secher, A. Rehman, S. Normand, A. De Arcangelis, R. Haesler, L. Huot, T. Grandjean, A. Bressenot, A. Delanoye-Crespin, et al. 2013. NOD2-mediated dysbiosis predisposes mice to transmissible colitis and colorectal cancer. J. Clin. Invest. 123:700-711. http://dx.doi.org/10.1172/JCI62236
16. Cuthbert, A.P., S.A. Fisher, M.M. Mirza, K. King, J. Hampe, P.J. Croucher, S. Mascheretti, J. Sanderson, A. Forbes, J. Mansfield, et al. 2002. The contribution of NOD2 gene mutations to the risk and site of disease in inflammatory bowel disease. Gastroenterology. 122:867-874. http://dx.doi.org/10.1053/gast.2002.32415
17. Darfeuille-Michaud, A., J. Boudeau, P. Bulois, C. Neut, A.L. Glasser, N. Barnich, M.A. Bringer, A. Swidsinski, L. Beaugerie, and J.F. Colombel. 2004. High prevalence of adherent-invasive Escherichia coli associated with ileal mucosa in Crohn's disease. Gastroenterology. 127:412-421. http://dx.doi.org/10.1053/j.gastro.2004.04.061
18. Deuring, J.J., G.M. Fuhler, S.R. Konstantinov, M.P. Peppelenbosch, E.J. Kuipers, C. de Haar, and C.J. van der Woude. 2014. Genomic ATG16L1 risk allele-restricted Paneth cell ER stress in quiescent Crohn's disease. Gut. 63:1081-1091. http://dx.doi.org/10.1136/gutjnl-2012-303527
19. Edgar, R.C., B.J. Haas, J.C. Clemente, C. Quince, and R. Knight. 2011. UCH IME improves sensitivity and speed of chimera detection. Bioinformatics. 27:2194-2200. http://dx.doi.org/10.1093/bioinformatics/btr381
20. Elinav, E., T. Strowig, A.L. Kau, J. Henao-Mejia, C.A. Thaiss, C.J. Booth, D.R. Peaper, J. Bertin, S.C. Eisenbarth, J.I. Gordon, and R.A. Flavell. 2011. NLRP6 inflammasome regulates colonic microbial ecology and risk for colitis. Cell. 145:745-757. http://dx.doi.org/10.1016/j.cell.2011.04.022
21. Ellinghaus, D., H. Zhang, S. Zeissig, S. Lipinski, A. Till, T. Jiang, B. Stade, Y. Bromberg, E. Ellinghaus, A. Keller, et al. 2013. Association between variants of PRDM1 and NDP52 and Crohn's disease, based on exome sequencing and functional studies. Gastroenterology. 145:339-347. http://dx.doi.org/10.1053/j.gastro.2013.04.040
22. Frank, D.N., A.L. St Amand, R.A. Feldman, E.C. Boedeker, N. Harpaz, and N.R. Pace. 2007. Molecular-phylogenetic characterization of microbial community imbalances in human inflammatory bowel diseases. Proc. Natl. Acad. Sci. USA. 104:13780-13785. http://dx.doi.org/10.1073/pnas.0706625104
23. Gao, B., S.M. Lee, A. Chen, J. Zhang, D.D. Zhang, K. Kannan, R.A. Ortmann, and D. Fang. 2008. Synoviolin promotes IRE1 ubiquitination and degradation in synovial fibroblasts from mice with collagen-induced arthritis. EMBO Rep. 9:480-485. http://dx.doi.org/10.1038/embor.2008.37
24. Garrett, W.S., G.M. Lord, S. Punit, G. Lugo-Villarino, S.K. Mazmanian, S. Ito, J.N. Glickman, and L.H. Glimcher. 2007. Communicable ulcerative colitis induced by T-bet deficiency in the innate immune system. Cell. 131:33-45. http://dx.doi.org/10.1016/j.cell.2007.08.017
25. Gevers, D., S. Kugathasan, L.A. Denson, Y. Vázquez-Baeza, W. Van Treuren, B. Ren, E. Schwager, D. Knights, S.J. Song, M. Yassour, et al. 2014. The treatment-naive microbiome in new-onset Crohn's disease. Cell Host Microbe. 15:382-392. http://dx.doi.org/10.1016/j.chom.2014.02.005
26. Ghosh, R., L. Wang, E.S. Wang, B.G. Perera, A. Igbaria, S. Morita, K. Prado, M. Thamsen, D. Caswell, H. Macias, et al. 2014. Allosteric inhibition of the IRE1α RNase preserves cell viability and function during endoplasmic reticulum stress. Cell. 158:534-548. http://dx.doi.org/10.1016/j.cell.2014.07.002
27. Hampe, J., A. Franke, P. Rosenstiel, A. Till, M. Teuber, K. Huse, M. Albrecht, G. Mayr, F.M. De La Vega, J. Briggs, et al. 2007. A genome-wide association scan of nonsynonymous SNPs identifies a susceptibility variant for Crohn disease in ATG16L1. Nat. Genet. 39:207-211. http://dx.doi.org/10.1038/ng1954
28. Han, J., S.H. Back, J. Hur, Y.H. Lin, R. Gildersleeve, J. Shan, C.L. Yuan, D. Krokowski, S. Wang, M. Hatzoglou, et al. 2013. ER-stress-induced transcriptional regulation increases protein synthesis leading to cell death. Nat. Cell Biol. 15:481-490. http://dx.doi.org/10.1038/ncb2738
29. Hetz, C., F. Martinon, D. Rodriguez, and L.H. Glimcher. 2011. The unfolded protein response: integrating stress signals through the stress sensor IRE1α. Physiol. Rev. 91:1219-1243. http://dx.doi.org/10.1152/physrev.00001.2011
30. Hodin, C.M., F.J. Verdam, J. Grootjans, S.S. Rensen, F.K. Verheyen, C.H. Dejong, W.A. Buurman, J.W. Greve, and K. Lenaerts. 2011. Reduced Paneth cell antimicrobial protein levels correlate with activation of the unfolded protein response in the gut of obese individuals. J. Pathol. 225:276-284. http://dx.doi.org/10.1002/path.2917
31. Homer, C.R., A.L. Richmond, N.A. Rebert, J.P. Achkar, and C. McDonald. 2010. ATG16L1 and NOD2 interact in an autophagy-dependent antibacterial pathway implicated in Crohn's disease pathogenesis. Gastroenterology. 139:1630-1641.e2. http://dx.doi.org/10.1053/j.gastro.2010.07.006
32. Hotamisligil, G.S. 2010. Endoplasmic reticulum stress and the inflammatory basis of metabolic disease. Cell. 140:900-917. http://dx.doi.org/10.1016/j.cell.2010.02.034
33. Iqbal, J., K. Dai, T. Seimon, R. Jungreis, M. Oyadomari, G. Kuriakose, D. Ron, I. Tabas, and M.M. Hussain. 2008. IRE1β inhibits chylomicron production by selectively degrading MTP mRNA. Cell Metab. 7:445-455. http://dx.doi.org/10.1016/j.cmet.2008.03.005
34. Iwakoshi, N.N., A.H. Lee, P. Vallabhajosyula, K.L. Otipoby, K. Rajewsky, and L.H. Glimcher. 2003. Plasma cell differentiation and the unfolded protein response intersect at the transcription factor XBP-1. Nat. Immunol. 4:321-329. http://dx.doi.org/10.1038/ni907
35. Iwawaki, T., A. Hosoda, T. Okuda, Y. Kamigori, C. Nomura-Furuwatari, Y. Kimata, A. Tsuru, and K. Kohno. 2001. Translational control by the ER transmembrane kinase/ribonuclease IRE1 under ER stress. Nat. Cell Biol. 3:158-164. http://dx.doi.org/10.1038/35055065
36. Jostins, L., S. Ripke, R.K. Weersma, R.H. Duerr, D.P. McGovern, K.Y. Hui, J.C. Lee, L.P. Schumm, Y. Sharma, C.A. Anderson, et al. International IBD Genetics Consortium. 2012. Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature. 491:119-124. http://dx.doi.org/10.1038/nature11582
37. Kaser, A., A.H. Lee, A. Franke, J.N. Glickman, S. Zeissig, H. Tilg, E.E. Nieuwenhuis, D.E. Higgins, S. Schreiber, L.H. Glimcher, and R.S. Blumberg. 2008. XBP1 links ER stress to intestinal inflammation and confers genetic risk for human inflammatory bowel disease. Cell. 134:743-756. http://dx.doi.org/10.1016/j.cell.2008.07.021
38. Keestra-Gounder, A.M., M.X. Byndloss, N. Seyffert, B.M. Young, A. Chávez-Arroyo, A.Y. Tsai, S.A. Cevallos, M.G. Winter, O.H. Pham, C.R. Tiffany, et al. 2016. NOD1 and NOD2 signalling links ER stress with inflammation. Nature. 532:394-397. http://dx.doi.org/10.1038/nature17631
39. Khalili, H., A.N. Ananthakrishnan, G.G. Konijeti, L.M. Higuchi, C.S. Fuchs, J.M. Richter, and A.T. Chan. 2015. Measures of obesity and risk of Crohn's disease and ulcerative colitis. Inflamm. Bowel Dis. 21:361-368. http://dx.doi.org/10.1097/MIB.0000000000000283
40. Khaminets, A., T. Heinrich, M. Mari, P. Grumati, A.K. Huebner, M. Akutsu, L. Liebmann, A. Stolz, S. Nietzsche, N. Koch, et al. 2015. Regulation of endoplasmic reticulum turnover by selective autophagy. Nature. 522:354-358. http://dx.doi.org/10.1038/nature14498
41. Khaminets, A., C. Behl, and I. Dikic. 2016. Ubiquitin-dependent and independent signals in selective autophagy. Trends Cell Biol. 26:6-16. http://dx.doi.org/10.1016/j.tcb.2015.08.010
42. Kobayashi, K.S., M. Chamaillard, Y. Ogura, O. Henegariu, N. Inohara, G. Nuñez, and R.A. Flavell. 2005. Nod2-dependent regulation of innate and adaptive immunity in the intestinal tract. Science. 307:731-734. http://dx.doi.org/10.1126/science.1104911
43. Korennykh, A., and P. Walter. 2012. Structural basis of the unfolded protein response. Annu. Rev. Cell Dev. Biol. 28:251-277. http://dx.doi.org/10.1146/annurev-cellbio-101011-155826
44. Kozich, J.J., S.L. Westcott, N.T. Baxter, S.K. Highlander, and P.D. Schloss. 2013. Development of a dual-index sequencing strategy and curation pipeline for analyzing amplicon sequence data on the MiSeq Illumina sequencing platform. Appl. Environ. Microbiol. 79:5112-5120. http://dx.doi.org/10.1128/AEM.01043-13
45. Lapaquette, P., A.L. Glasser, A. Huett, R.J. Xavier, and A. Darfeuille-Michaud. 2010. Crohn's disease-associated adherent-invasive E. coli are selectively favoured by impaired autophagy to replicate intracellularly. Cell. Microbiol. 12:99-113. http://dx.doi.org/10.1111/j.1462-5822.2009.01381.x
46. Lee, K., W. Tirasophon, X. Shen, M. Michalak, R. Prywes, T. Okada, H. Yoshida, K. Mori, and R.J. Kaufman. 2002. IRE1-mediated unconventional mRNA splicing and S2P-mediated ATF6 cleavage merge to regulate XBP1 in signaling the unfolded protein response. Genes Dev. 16:452-466. http://dx.doi.org/10.1101/gad.964702
47. Levine, B., N. Mizushima, and H.W. Virgin. 2011. Autophagy in immunity and inflammation. Nature. 469:323-335. http://dx.doi.org/10.1038/nature09782
48. Li, H., A.V. Korennykh, S.L. Behrman, and P. Walter. 2010. Mammalian endoplasmic reticulum stress sensor IRE1 signals by dynamic clustering. Proc. Natl. Acad. Sci. USA. 107:16113-16118. http://dx.doi.org/10.1073/pnas.1010580107
49. Liu, B., A.S. Gulati, V. Cantillana, S.C. Henry, E.A. Schmidt, X. Daniell, E. Grossniklaus, A.A. Schoenborn, R.B. Sartor, and G.A. Taylor. 2013. Irgm1-deficient mice exhibit Paneth cell abnormalities and increased susceptibility to acute intestinal inflammation. Am. J. Physiol. Gastrointest. Liver Physiol. 305:G573-G584. http://dx.doi.org/10.1152/ajpgi.00071.2013
50. Liu, J.Z., S. van Sommeren, H. Huang, S.C. Ng, R. Alberts, A. Takahashi, S. Ripke, J.C. Lee, L. Jostins, T. Shah, et al. International IBD Genetics Consortium. 2015. Association analyses identify 38 susceptibility loci for inflammatory bowel disease and highlight shared genetic risk across populations. Nat. Genet. 47:979-986. http://dx.doi.org/10.1038/ng.3359
51. Maloy, K.J., and F. Powrie. 2011. Intestinal homeostasis and its breakdown in inflammatory bowel disease. Nature. 474:298-306. http://dx.doi.org/10.1038/nature10208
52. Martino, M.B., L. Jones, B. Brighton, C. Ehre, L. Abdulah, C.W. Davis, D. Ron, W.K. O'Neal, and C.M. Ribeiro. 2013. The ER stress transducer IRE1β is required for airway epithelial mucin production. Mucosal Immunol. 6:639-654. http://dx.doi.org/10.1038/mi.2012.105
53. Maurel, M., E. Chevet, J. Tavernier, and S. Gerlo. 2014. Getting RIDD of RNA: IRE1 in cell fate regulation. Trends Biochem. Sci. 39:245-254. http://dx.doi.org/10.1016/j.tibs.2014.02.008
54. McArdle, B.H., and M.J. Anderson. 2001. Fitting multivariate models to community data: A comment on distance-based redundancy analysis. Ecology. 82:290-297. http://dx.doi.org/10.1890/0012-9658(2001)082[0290:FMM TCD]2.0.CO;2
55. Molodecky, N.A., I.S. Soon, D.M. Rabi, W.A. Ghali, M. Ferris, G. Chernoff, E.I. Benchimol, R. Panaccione, S. Ghosh, H.W. Barkema, and G.G. Kaplan. 2012. Increasing incidence and prevalence of the inflammatory bowel diseases with time, based on systematic review. Gastroenterology. 142:46-54.e42. http://dx.doi.org/10.1053/j.gastro.2011.10.001
56. Murthy, A., Y. Li, I. Peng, M. Reichelt, A.K. Katakam, R. Noubade, M. Roose-Girma, J. DeVoss, L. Diehl, R.R. Graham, and M. van Lookeren Campagne. 2014. A Crohn's disease variant in Atg16l1 enhances its degradation by caspase 3. Nature. 506:456-462. http://dx.doi.org/10.1038/nature13044
57. Nezami, B.G., S.M. Mwangi, J.E. Lee, S. Jeppsson, M. Anitha, S.S. Yarandi, A.B. Farris III, and S. Srinivasan. 2014. MicroRNA 375 mediates palmitateinduced enteric neuronal damage and high-fat diet-induced delayed intestinal transit in mice. Gastroenterology. 146:473-83.e3. http://dx.doi.org/10.1053/j.gastro.2013.10.053
58. Niederreiter, L., T.M. Fritz, T.E. Adolph, A.M. Krismer, F.A. Offner, M. Tschurtschenthaler, M.B. Flak, S. Hosomi, M.F. Tomczak, N.C. Kaneider, et al. 2013. ER stress transcription factor Xbp1 suppresses intestinal tumorigenesis and directs intestinal stem cells. J. Exp. Med. 210:2041-2056. http://dx.doi.org/10.1084/jem.20122341
59. Pillich, H., M. Loose, K.P. Zimmer, and T. Chakraborty. 2012. Activation of the unfolded protein response by Listeria monocytogenes. Cell. Microbiol. 14:949-964. http://dx.doi.org/10.1111/j.1462-5822.2012.01769.x
60. Powell, N., A.W. Walker, E. Stolarczyk, J.B. Canavan, M.R. Gökmen, E. Marks, I. Jackson, A. Hashim, M.A. Curtis, R.G. Jenner, et al. 2012. The transcription factor T-bet regulates intestinal inflammation mediated by interleukin-7 receptor+ innate lymphoid cells. Immunity. 37:674-684. http://dx.doi.org/10.1016/j.immuni.2012.09.008
61. Prescott, N.J., S.A. Fisher, A. Franke, J. Hampe, C.M. Onnie, D. Soars, R. Bagnall, M.M. Mirza, J. Sanderson, A. Forbes, et al. 2007. A nonsynonymous SNP in ATG16L1 predisposes to ileal Crohn's disease and is independent of CARD15 and IBD5. Gastroenterology. 132:1665-1671. http://dx.doi.org/10.1053/j.gastro.2007.03.034
62. Quast, C., E. Pruesse, P. Yilmaz, J. Gerken, T. Schweer, P. Yarza, J. Peplies, and F.O. Glöckner. 2013. The SIL VA ribosomal RNA gene database project: improved data processing and web-based tools. Nucleic Acids Res. 41:D590-D596. http://dx.doi.org/10.1093/nar/gks1219
63. Rehman, A., P. Rausch, J. Wang, J. Skieceviciene, G. Kiudelis, K. Bhagalia, D. Amarapurkar, L. Kupcinskas, S. Schreiber, P. Rosenstiel, et al. 2016. Geographical patterns of the standing and active human gut microbiome in health and IBD. Gut. 65:238-248. http://dx.doi.org/10.1136/gutjnl-2014-308341
64. Rioux, J.D., R.J. Xavier, K.D. Taylor, M.S. Silverberg, P. Goyette, A. Huett, T. Green, P. Kuballa, M.M. Barmada, L.W. Datta, et al. 2007. Genome-wide association study identifies new susceptibility loci for Crohn disease and implicates autophagy in disease pathogenesis. Nat. Genet. 39:596-604. http://dx.doi.org/10.1038/ng2032
65. Rogov, V., V. Dötsch, T. Johansen, and V. Kirkin. 2014. Interactions between autophagy receptors and ubiquitin-like proteins form the molecular basis for selective autophagy. Mol. Cell. 53:167-178. http://dx.doi.org/10.1016/j.molcel.2013.12.014
66. Sato, T., R.G. Vries, H.J. Snippert, M. van de Wetering, N. Barker, D.E. Stange, J.H. van Es, A. Abo, P. Kujala, P.J. Peters, and H. Clevers. 2009. Single Lgr5 stem cells build crypt-villus structures in vitro without a mesenchymal niche. Nature. 459:262-265. http://dx.doi.org/10.1038/nature07935
67. Schaubeck, M., T. Clavel, J. Calasan, I. Lagkouvardos, S.B. Haange, N. Jehmlich, M. Basic, A. Dupont, M. Hornef, M. von Bergen, et al. 2016. Dysbiotic gut microbiota causes transmissible Crohn's disease-like ileitis independent of failure in antimicrobial defence. Gut. 65:225-237. http://dx.doi.org/10.1136/gutjnl-2015-309333
68. Schloss, P.D., S.L. Westcott, T. Ryabin, J.R. Hall, M. Hartmann, E.B. Hollister, R.A. Lesniewski, B.B. Oakley, D.H. Parks, C.J. Robinson, et al. 2009. Introducing mothur: open-source, platform-independent, community-supported software for describing and comparing microbial communities. Appl. Environ. Microbiol. 75:7537-7541. http://dx.doi.org/10.1128/AEM.01541-09
69. Schuck, S., C.M. Gallagher, and P. Walter. 2014. ER-phagy mediates selective degradation of endoplasmic reticulum independently of the core autophagy machinery. J. Cell Sci. 127:4078-4088. http://dx.doi.org/10.1242/jcs.154716
70. Simpson, K.W., B. Dogan, M. Rishniw, R.E. Goldstein, S. Klaessig, P.L. McDonough, A.J. German, R.M. Yates, D.G. Russell, S.E. Johnson, et al. 2006. Adherent and invasive Escherichia coli is associated with granulomatous colitis in boxer dogs. Infect. Immun. 74:4778-4792. http://dx.doi.org/10.1128/IAI.00067-06
71. Smith, A.M., G.W. Sewell, A.P. Levine, T.S. Chew, J. Dunne, N.R. O'Shea, P.J. Smith, P.J. Harrison, C.M. Macdonald, S.L. Bloom, and A.W. Segal. 2015. Disruption of macrophage pro-inflammatory cytokine release in Crohn's disease is associated with reduced optineurin expression in a subset of patients. Immunology. 144:45-55. http://dx.doi.org/10.1111/imm.12338
72. Stancu, C.S., M.G. Carnuta, G.M. Sanda, L. Toma, M. Deleanu, L.S. Niculescu, S. Sasson, M. Simionescu, and A.V. Sima. 2015. Hyperlipidemia-induced hepatic and small intestine ER stress and decreased paraoxonase 1 expression and activity is associated with HDL dysfunction in Syrian hamsters. Mol. Nutr. Food Res. 59:2293-2302. http://dx.doi.org/10.1002/mnfr.201500422
73. Stolz, A., A. Ernst, and I. Dikic. 2014. Cargo recognition and trafficking in selective autophagy. Nat. Cell Biol. 16:495-501. http://dx.doi.org/10.1038/ncb2979
74. Sun, C., H. Wang, S. Chen, Z. Li, S. Li, and J. Wang. 2014. Recombinant Clostridium difficile toxin B induces endoplasmic reticulum stress in mouse colonal carcinoma cells. Acta Biochim. Biophys. Sin. (Shanghai). 46:973-981. http://dx.doi.org/10.1093/abbs/gmu091
75. Sun, S., G. Shi, H. Sha, Y. Ji, X. Han, X. Shu, H. Ma, T. Inoue, B. Gao, H. Kim, et al. 2015. IRE1α is an endogenous substrate of endoplasmicreticulum-associated degradation. Nat. Cell Biol. 17:1546-1555. http://dx.doi.org/10.1038/ncb3266
76. Tashiro, E., N. Hironiwa, M. Kitagawa, Y. Futamura, S. Suzuki, M. Nishio, and M. Imoto. 2007. Trierixin, a novel Inhibitor of ER stress-induced XBP1 activation from Streptomyces sp. 1. Taxonomy, fermentation, isolation, and biological activities. J. Antibiot. 60:547-553. http://dx.doi.org/10.1038/ja.2007.69
77. Taylor, R.C., and A. Dillin. 2013. XBP-1 is a cell-nonautonomous regulator of stress resistance and longevity. Cell. 153:1435-1447. http://dx.doi.org/10.1016/j.cell.2013.05.042
78. Tirasophon, W., K. Lee, B. Callaghan, A. Welihinda, and R.J. Kaufman. 2000. The endoribonuclease activity of mammalian IRE1 autoregulates its mRNA and is required for the unfolded protein response. Genes Dev. 14:2725-2736. http://dx.doi.org/10.1101/gad.839400
79. Travassos, L.H., L.A. Carneiro, M. Ramjeet, S. Hussey, Y.G. Kim, J.G. Magalhães, L. Yuan, F. Soares, E. Chea, L. Le Bourhis, 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. http://dx.doi.org/10.1038/ni.1823
80. Tsuru, A., N. Fujimoto, S. Takahashi, M. Saito, D. Nakamura, M. Iwano, T. Iwawaki, H. Kadokura, D. Ron, and K. Kohno. 2013. Negative feedback by IRE1β optimizes mucin production in goblet cells. Proc. Natl. Acad. Sci. USA. 110:2864-2869. http://dx.doi.org/10.1073/pnas.1212484110
81. VanDussen, K.L., T.C. Liu, D. Li, F. Towfic, N. Modiano, R. Winter, T. Haritunians, K.D. Taylor, D. Dhall, S.R. Targan, et al. 2014. Genetic variants synthesize to produce paneth cell phenotypes that define subtypes of Crohn's disease. Gastroenterology. 146:200-209. http://dx.doi.org/10.1053/j.gastro.2013.09.048
82. Walter, P., and D. Ron. 2011. The unfolded protein response: from stress pathway to homeostatic regulation. Science. 334:1081-1086. http://dx.doi.org/10.1126/science.1209038
83. Wang, M., and R.J. Kaufman. 2016. Protein misfolding in the endoplasmic reticulum as a conduit to human disease. Nature. 529:326-335. http://dx.doi.org/10.1038/nature17041
84. Wang, Q., G.M. Garrity, J.M. Tiedje, and J.R. Cole. 2007. Naive Bayesian classifier for rapid assignment of rRNA sequences into the new bacterial taxonomy. Appl. Environ. Microbiol. 73:5261-5267. http://dx.doi.org/10.1128/AEM.00062-07
85. Wehkamp, J., N.H. Salzman, E. Porter, S. Nuding, M. Weichenthal, R.E. Petras, B. Shen, E. Schaeffeler, M. Schwab, R. Linzmeier, et al. 2005. Reduced Paneth cell α-defensins in ileal Crohn's disease. Proc. Natl. Acad. Sci. USA. 102:18129-18134. http://dx.doi.org/10.1073/pnas.0505256102
86. Weidberg, H., E. Shvets, and Z. Elazar. 2011. Biogenesis and cargo selectivity of autophagosomes. Annu. Rev. Biochem. 80:125-156. http://dx.doi.org/10.1146/annurev-biochem-052709-094552
87. Wild, P., H. Farhan, D.G. McEwan, S. Wagner, V.V. Rogov, N.R. Brady, B. Richter, J. Korac, O. Waidmann, C. Choudhary, et al. 2011. Phosphorylation of the autophagy receptor optineurin restricts Salmonella growth. Science. 333:228-233. http://dx.doi.org/10.1126/science.1205405
88. Woehlbier, U., and C. Hetz. 2011. Modulating stress responses by the UPRosome: a matter of life and death. Trends Biochem. Sci. 36:329-337. http://dx.doi.org/10.1016/j.tibs.2011.03.001
89. Yin, J., L. Gu, Y. Wang, N. Fan, Y. Ma, and Y. Peng. 2015. Rapamycin improves palmitate-induced ER stress/NFκB pathways associated with stimulating autophagy in adipocytes. Mediators Inflamm. 2015:272313. http://dx.doi.org/10.1155/2015/272313
90. Zhang, Q., Y. Pan, R. Yan, B. Zeng, H. Wang, X. Zhang, W. Li, H. Wei, and Z. Liu. 2015. Commensal bacteria direct selective cargo sorting to promote symbiosis. Nat. Immunol. 16:918-926. http://dx.doi.org/10.1038/ni.3233
91. Zhu, X., J. Zhang, H. Sun, C. Jiang, Y. Dong, Q. Shan, S. Su, Y. Xie, N. Xu, X. Lou, and S. Liu. 2014. Ubiquitination of inositol-requiring enzyme 1 (IRE1) by the E3 ligase CHIP mediates the IRE1/TRAF2/JNK pathway. J. Biol. Chem. 289:30567-30577. http://dx.doi.org/10.1074/jbc.M114.562868