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The unfolded protein response and gastrointestinal disease

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Abstract

As the inner lining of the gastrointestinal tract, the intestinal epithelium serves an essential role in innate immune function at the interface between the host and microbiota. Given the unique environmental challenges and thus physiologic secretory functions of this surface, it is exquisitely sensitive to perturbations that affect its capacity to resolve endoplasmic reticulum (ER) stress. Genetic deletion of factors involved in the unfolded protein response (UPR), which functions in the resolution of ER stress that arises from misfolded proteins, result in spontaneous intestinal inflammation closely mimicking human inflammatory bowel disease (IBD). This is demonstrated by observations wherein deletion of genes such as Xbp1 and Agr2 profoundly affects the intestinal epithelium and results in spontaneous intestinal inflammation. Moreover, both genes, along with others (e.g., ORDML3) represent genetic risk factors for human IBD, both Crohn's disease and ulcerative colitis. Here, we review the current mechanistic understanding for how unresolved ER stress can lead to intestinal inflammation and highlight the findings that implicate ER stress as a genetically affected biological pathway in IBD. We further discuss environmental and microbial factors that might impact on the epithelium's capacity to resolve ER stress and which may constitute exogenous factors that may precipitate disease in genetically susceptible individuals.

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Abbreviations

ABCG2:

ATP-binding cassette G2

AIDS:

Acquired immunodeficiency syndrome

AIEC:

Adherent-invasive Escherichia coli

AGR2:

Anterior gradient 2

ASK1:

Apoptosis signal-regulating kinase 1

ATF4:

Activating transcription factor 4

ATF6:

Activating transcription factor 6

BAK:

BCL2-antagonist/killer 1

BAX:

BCL2-associated X protein

BBF2H7:

Box B-binding factor 2 human homolog on chromosome 7

BiP:

Binding immunoglobulin protein

CD:

Crohn's disease

CEACAM6:

Carcinoembryonic antigen-related cell adhesion molecule 6

CHOP:

C/EBP homologous protein

CREB4:

CRE-binding protein 4

CREBH:

CRE-binding protein H

C/EBP:

CCAAT/enhancer-binding protein

DSS:

Dextran sodium sulfate

eIF2α:

Elongation initiation factor 2α

ER:

Endoplasmic reticulum

EDEM1:

ER degradation enhancer, mannosidase alpha-like 1

ENU:

N-ethyl-N-nitrosourea

ERAD:

ER-associated degradation

GADD34:

Growth arrest and DNA damage-inducible protein 34

grp78:

78kDa glucose-regulated protein

Grp94:

Glucose regulated protein 94

HIV:

Human immunodeficiency virus

IBD:

Inflammatory bowel disease

IEC:

Intestinal epithelial cell

IRE1:

Inositol-requiring enzyme 1

IEL:

Intraepithelial lymphocyte

JNK:

Jun N-terminal kinase

lZIP:

Leucine zipper protein

MEF:

Mouse embryonic fibroblast

MTP:

Microsomal triglyceride transfer protein

MSI1:

Musashi-1

OASIS:

Old astrocyte specifically induced substance

ORMDL3:

Orosomucoid-like 3

PERK:

Protein kinase related (PKR)-like ER kinase

P58IPK :

Protein kinase inhibitor of 58 kDa

PBA:

4-phenyl butyrate

RIDD:

Regulated IRE1-dependent decay

S1P:

Site-1 protease

S2P:

Site-2 protease

SPF:

Specific pathogen-free

SERCA2b:

Sarcoplasmic/endoplasmic reticulum calcium ATPase 2

SERCA:

Sarco-endoplasmic reticulum Ca2+ pump

TNBS:

Trinitrobenzene sulfonic acid

TNF:

Tumor necrosis factor

TRAF2:

TNF receptor associated factor 2

TNFR1:

Tumor necrosis factor receptor type 1

TLR:

Toll-like receptor

TUDCA:

Tauro-ursodeoxycholic acid

UC:

Ulcerative colitis

UDCA:

Ursodeoxy-cholic acid

uORF:

Upstream open reading frame

UTR:

5' untranslated region

UPR:

Unfolded protein response

VLDL:

Very low density lipoprotein

XBP1:

X-box binding protein-1

References

  1. Pott J, Hornef M (2012) Innate immune signalling at the intestinal epithelium in homeostasis and disease. EMBO Rep 13:684–698

    PubMed  CAS  Google Scholar 

  2. van der Flier LG, Clevers H (2009) Stem cells, self-renewal, and differentiation in the intestinal epithelium. Annu Rev Physiol 71:241–260

    PubMed  Google Scholar 

  3. Barker N, van Es JH, Kuipers J, Kujala P, van den Born M, Cozijnsen M et al (2007) Identification of stem cells in small intestine and colon by marker gene Lgr5. Nature 449:1003–1007

    PubMed  CAS  Google Scholar 

  4. Sato T, van Es JH, Snippert HJ, Stange DE, Vries RG, van den Born M et al (2011) Paneth cells constitute the niche for Lgr5 stem cells in intestinal crypts. Nature 469:415–418

    PubMed  CAS  Google Scholar 

  5. Rothenberg ME, Nusse Y, Kalisky T, Lee JJ, Dalerba P, Scheeren F et al (2012) Identification of a Ckit+ Colonic Crypt Base Secretory Cell that Supports Lgr5+ Stem Cells in Mice. Gastroenterology 142:1195–1205

    Google Scholar 

  6. Hansson GC (2012) Role of mucus layers in gut infection and inflammation. Curr Opin Microbiol 15:57–62

    PubMed  CAS  Google Scholar 

  7. Kaser A, Zeissig S, Blumberg RS (2010) Inflammatory bowel disease. Annu Rev Immunol 28:573–621

    PubMed  CAS  Google Scholar 

  8. Pukkila-Worley R, Ausubel FM (2012) Immune defense mechanisms in the Caenorhabditis elegans intestinal epithelium. Curr Opin Immunol 24:3–9

    PubMed  CAS  Google Scholar 

  9. Kaser A, Blumberg RS (2010) Endoplasmic reticulum stress and intestinal inflammation. Mucosal Immunol 3:11–16

    PubMed  CAS  Google Scholar 

  10. Walter P, Ron D (2011) The unfolded protein response: from stress pathway to homeostatic regulation. Science 334:1081–1086

    PubMed  CAS  Google Scholar 

  11. Schroder M, Kaufman RJ (2005) The mammalian unfolded protein response. Annu Rev Biochem 74:739–789

    PubMed  Google Scholar 

  12. Todd DJ, Lee AH, Glimcher LH (2008) The endoplasmic reticulum stress response in immunity and autoimmunity. Nat Rev Immunol 8:663–674

    PubMed  CAS  Google Scholar 

  13. Bertolotti A, Wang X, Novoa I, Jungreis R, Schlessinger K, Cho JH et al (2001) Increased sensitivity to dextran sodium sulfate colitis in IRE1beta-deficient mice. J Clin Invest 107:585–593

    PubMed  CAS  Google Scholar 

  14. Hetz C, Martinon F, Rodriguez D, Glimcher LH (2011) The unfolded protein response: integrating stress signals through the stress sensor IRE1alpha. Physiol Rev 91:1219–1243

    PubMed  CAS  Google Scholar 

  15. Hollien J, Weissman JS (2006) Decay of endoplasmic reticulum-localized mRNAs during the unfolded protein response. Science 313:104–107

    PubMed  CAS  Google Scholar 

  16. Acosta-Alvear D, Zhou Y, Blais A, Tsikitis M, Lents NH, Arias C et al (2007) XBP1 controls diverse cell type- and condition-specific transcriptional regulatory networks. Mol Cell 27:53–66

    PubMed  CAS  Google Scholar 

  17. Iwawaki T, Akai R, Kohno K, Miura M (2004) A transgenic mouse model for monitoring endoplasmic reticulum stress. Nat Med 10:98–102

    PubMed  CAS  Google Scholar 

  18. 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 134:743–756

    PubMed  CAS  Google Scholar 

  19. Zhao F, Edwards R, Dizon D, Afrasiabi K, Mastroianni JR, Geyfman M et al (2010) Disruption of Paneth and goblet cell homeostasis and increased endoplasmic reticulum stress in Agr2−/− mice. Dev Biol 338:270–279

    PubMed  CAS  Google Scholar 

  20. Schwitalla S, Fingerle AA, Cammareri P, Nebelsiek T, Goktuna SI, Ziegler PK et al (2013) Intestinal tumorigenesis initiated by dedifferentiation and acquisition of stem-cell-like properties. Cell 152:25–38

    PubMed  CAS  Google Scholar 

  21. Woehlbier U, Hetz C (2011) Modulating stress responses by the UPRosome: a matter of life and death. Trends Biochem Sci 36:329–337

    PubMed  CAS  Google Scholar 

  22. Hetz C, Bernasconi P, Fisher J, Lee AH, Bassik MC, Antonsson B et al (2006) Proapoptotic BAX and BAK modulate the unfolded protein response by a direct interaction with IRE1alpha. Science 312:572–576

    PubMed  CAS  Google Scholar 

  23. Urano F, Wang X, Bertolotti A, Zhang Y, Chung P, Harding HP et al (2000) Coupling of stress in the ER to activation of JNK protein kinases by transmembrane protein kinase IRE1. Science 287:664–666

    PubMed  CAS  Google Scholar 

  24. Yang Q, Kim YS, Lin Y, Lewis J, Neckers L, Liu ZG (2006) Tumour necrosis factor receptor 1 mediates endoplasmic reticulum stress-induced activation of the MAP kinase JNK. EMBO Rep 7:622–627

    PubMed  CAS  Google Scholar 

  25. Iqbal J, Dai K, Seimon T, Jungreis R, Oyadomari M, Kuriakose G et al (2008) IRE1beta inhibits chylomicron production by selectively degrading MTP mRNA. Cell Metab 7:445–455

    PubMed  CAS  Google Scholar 

  26. Hussain MM, Fatma S, Pan X, Iqbal J (2005) Intestinal lipoprotein assembly. Curr Opin Lipidol 16:281–285

    PubMed  CAS  Google Scholar 

  27. Lee AH, Scapa EF, Cohen DE, Glimcher LH (2008) Regulation of hepatic lipogenesis by the transcription factor XBP1. Science 320:1492–1496

    PubMed  CAS  Google Scholar 

  28. Wang S, Chen Z, Lam V, Han J, Hassler J, Finck BN et al (2012) IRE1alpha-XBP1s induces PDI expression to increase MTP activity for hepatic VLDL assembly and lipid homeostasis. Cell Metab 16:473–486

    PubMed  CAS  Google Scholar 

  29. So JS, Hur KY, Tarrio M, Ruda V, Frank-Kamenetsky M, Fitzgerald K et al (2012) Silencing of lipid metabolism genes through IRE1alpha-mediated mRNA decay lowers plasma lipids in mice. Cell Metab 16:487–499

    PubMed  CAS  Google Scholar 

  30. Fisher EA, Brodsky JL (2012) The unfolded protein response: a multifaceted regulator of lipid and lipoprotein metabolism. Cell Metab 16:407–408

    PubMed  CAS  Google Scholar 

  31. Brozovic S, Nagaishi T, Yoshida M, Betz S, Salas A, Chen D et al (2004) CD1d function is regulated by microsomal triglyceride transfer protein. Nat Med 10:535–539

    PubMed  CAS  Google Scholar 

  32. Dougan SK, Rava P, Hussain MM, Blumberg RS (2007) MTP regulated by an alternate promoter is essential for NKT cell development. J Exp Med 204:533–545

    PubMed  CAS  Google Scholar 

  33. Dougan SK, Salas A, Rava P, Agyemang A, Kaser A, Morrison J et al (2005) Microsomal triglyceride transfer protein lipidation and control of CD1d on antigen-presenting cells. J Exp Med 202:529–539

    PubMed  CAS  Google Scholar 

  34. Kaser A, Hava DL, Dougan SK, Chen Z, Zeissig S, Brenner MB et al (2008) Microsomal triglyceride transfer protein regulates endogenous and exogenous antigen presentation by group 1 CD1 molecules. Eur J Immunol 38:2351–2359

    PubMed  CAS  Google Scholar 

  35. Dougan SK, Kaser A, Blumberg RS (2007) CD1 expression on antigen-presenting cells. Curr Top Microbiol Immunol 314:113–141

    PubMed  CAS  Google Scholar 

  36. Heller F, Fuss IJ, Nieuwenhuis EE, Blumberg RS, Strober W (2002) Oxazolone colitis, a Th2 colitis model resembling ulcerative colitis, is mediated by IL-13-producing NK-T cells. Immunity 17:629–638

    PubMed  CAS  Google Scholar 

  37. Komiya T, Tanigawa Y, Hirohashi S (1999) Cloning of the gene gob-4, which is expressed in intestinal goblet cells in mice. Biochim Biophys Acta 1444:434–438

    PubMed  CAS  Google Scholar 

  38. Park SW, Zhen G, Verhaeghe C, Nakagami Y, Nguyenvu LT, Barczak AJ et al (2009) The protein disulfide isomerase AGR2 is essential for production of intestinal mucus. Proc Natl Acad Sci U S A 106:6950–6955

    PubMed  CAS  Google Scholar 

  39. Wang Z, Hao Y, Lowe AW (2008) The adenocarcinoma-associated antigen, AGR2, promotes tumor growth, cell migration, and cellular transformation. Cancer Res 68:492–497

    PubMed  CAS  Google Scholar 

  40. Ellgaard L, Ruddock LW (2005) The human protein disulphide isomerase family: substrate interactions and functional properties. EMBO Rep 6:28–32

    PubMed  CAS  Google Scholar 

  41. Johansson ME, Larsson JM, Hansson GC (2011) The two mucus layers of colon are organized by the MUC2 mucin, whereas the outer layer is a legislator of host–microbial interactions. Proc Natl Acad Sci U S A 108(Suppl 1):4659–4665

    PubMed  CAS  Google Scholar 

  42. McGuckin MA, Linden SK, Sutton P, Florin TH (2011) Mucin dynamics and enteric pathogens. Nat Rev Microbiol 9:265–278

    PubMed  CAS  Google Scholar 

  43. Zhang K, Kaufman RJ (2008) From endoplasmic-reticulum stress to the inflammatory response. Nature 454:455–462

    PubMed  CAS  Google Scholar 

  44. Wang S, Kaufman RJ (2012) The impact of the unfolded protein response on human disease. J Cell Biol 197:857–867

    PubMed  CAS  Google Scholar 

  45. Back SH, Kaufman RJ (2012) Endoplasmic reticulum stress and type 2 diabetes. Annu Rev Biochem 81:767–793

    PubMed  CAS  Google Scholar 

  46. Yamamoto K, Sato T, Matsui T, Sato M, Okada T, Yoshida H et al (2007) Transcriptional induction of mammalian ER quality control proteins is mediated by single or combined action of ATF6alpha and XBP1. Dev Cell 13:365–376

    PubMed  CAS  Google Scholar 

  47. Cao SS, Zimmermann EM, Chuang BM, Song B, Nwokoye A, Wilkinson JE et al (2013) The Unfolded Protein Response and Chemical Chaperones Reduce Protein Misfolding and Colitis in Mice. Gastroenterology. doi:10.1053/j.gastro.2013.01.023

  48. Rutkowski DT, Kang SW, Goodman AG, Garrison JL, Taunton J, Katze MG et al (2007) The role of p58IPK in protecting the stressed endoplasmic reticulum. Mol Biol Cell 18:3681–3691

    PubMed  CAS  Google Scholar 

  49. Petrova K, Oyadomari S, Hendershot LM, Ron D (2008) Regulated association of misfolded endoplasmic reticulum lumenal proteins with P58/DNAJc3. EMBO J 27:2862–2872

    PubMed  CAS  Google Scholar 

  50. Brandl K, Rutschmann S, Li X, Du X, Xiao N, Schnabl B et al (2009) Enhanced sensitivity to DSS colitis caused by a hypomorphic Mbtps1 mutation disrupting the ATF6-driven unfolded protein response. Proc Natl Acad Sci U S A 106:3300–3305

    PubMed  CAS  Google Scholar 

  51. Ye J, Rawson RB, Komuro R, Chen X, Dave UP, Prywes R et al (2000) ER stress induces cleavage of membrane-bound ATF6 by the same proteases that process SREBPs. Mol Cell 6:1355–1364

    PubMed  CAS  Google Scholar 

  52. Namba T, Tanaka K, Ito Y, Ishihara T, Hoshino T, Gotoh T et al (2009) Positive role of CCAAT/enhancer-binding protein homologous protein, a transcription factor involved in the endoplasmic reticulum stress response in the development of colitis. Am J Pathol 174:1786–1798

    PubMed  CAS  Google Scholar 

  53. Strober W, Fuss IJ, Blumberg RS (2002) The immunology of mucosal models of inflammation. Annu Rev Immunol 20:495–549

    PubMed  CAS  Google Scholar 

  54. Hue S, Ahern P, Buonocore S, Kullberg MC, Cua DJ, McKenzie BS et al (2006) Interleukin-23 drives innate and T cell-mediated intestinal inflammation. J Exp Med 203:2473–2483

    PubMed  CAS  Google Scholar 

  55. Izcue A, Hue S, Buonocore S, Arancibia-Carcamo CV, Ahern PP, Iwakura Y et al (2008) Interleukin-23 restrains regulatory T cell activity to drive T cell-dependent colitis. Immunity 28:559–570

    PubMed  CAS  Google Scholar 

  56. Maloy KJ, Powrie F (2011) Intestinal homeostasis and its breakdown in inflammatory bowel disease. Nature 474:298–306

    PubMed  CAS  Google Scholar 

  57. Buonocore S, Ahern PP, Uhlig HH, Ivanov II, Littman DR, Maloy KJ et al (2010) Innate lymphoid cells drive interleukin-23-dependent innate intestinal pathology. Nature 464:1371–1375

    PubMed  CAS  Google Scholar 

  58. Goodall JC, Wu C, Zhang Y, McNeill L, Ellis L, Saudek V et al (2010) Endoplasmic reticulum stress-induced transcription factor, CHOP, is crucial for dendritic cell IL-23 expression. Proc Natl Acad Sci U S A 107:17698–17703

    PubMed  CAS  Google Scholar 

  59. Heazlewood CK, Cook MC, Eri R, Price GR, Tauro SB, Taupin D et al (2008) Aberrant mucin assembly in mice causes endoplasmic reticulum stress and spontaneous inflammation resembling ulcerative colitis. PLoS Med 5:e54

    PubMed  Google Scholar 

  60. Van der Sluis M, De Koning BA, De Bruijn AC, Velcich A, Meijerink JP, Van Goudoever JB et al (2006) Muc2-deficient mice spontaneously develop colitis, indicating that MUC2 is critical for colonic protection. Gastroenterology 131:117–129

    PubMed  Google Scholar 

  61. Dougados M, Baeten D (2011) Spondyloarthritis. Lancet 377:2127–2137

    PubMed  Google Scholar 

  62. Hammer RE, Maika SD, Richardson JA, Tang JP, Taurog JD (1990) Spontaneous inflammatory disease in transgenic rats expressing HLA-B27 and human beta 2m: an animal model of HLA-B27-associated human disorders. Cell 63:1099–1112

    PubMed  CAS  Google Scholar 

  63. May E, Dorris ML, Satumtira N, Iqbal I, Rehman MI, Lightfoot E et al (2003) CD8 alpha beta T cells are not essential to the pathogenesis of arthritis or colitis in HLA-B27 transgenic rats. J Immunol 170:1099–1105

    PubMed  CAS  Google Scholar 

  64. Turner MJ, Sowders DP, DeLay ML, Mohapatra R, Bai S, Smith JA et al (2005) HLA-B27 misfolding in transgenic rats is associated with activation of the unfolded protein response. J Immunol 175:2438–2448

    PubMed  CAS  Google Scholar 

  65. DeLay ML, Turner MJ, Klenk EI, Smith JA, Sowders DP, Colbert RA (2009) HLA-B27 misfolding and the unfolded protein response augment interleukin-23 production and are associated with Th17 activation in transgenic rats. Arthritis Rheum 60:2633–2643

    PubMed  CAS  Google Scholar 

  66. Shkoda A, Ruiz PA, Daniel H, Kim SC, Rogler G, Sartor RB et al (2007) Interleukin-10 blocked endoplasmic reticulum stress in intestinal epithelial cells: impact on chronic inflammation. Gastroenterology 132:190–207

    PubMed  CAS  Google Scholar 

  67. Treton X, Pedruzzi E, Cazals-Hatem D, Grodet A, Panis Y, Groyer A et al (2011) Altered endoplasmic reticulum stress affects translation in inactive colon tissue from patients with ulcerative colitis. Gastroenterology 141:1024–1035

    PubMed  CAS  Google Scholar 

  68. Deuring JJ, de Haar C, Koelewijn CL, Kuipers EJ, Peppelenbosch MP, van der Woude CJ (2012) Absence of ABCG2-mediated mucosal detoxification in patients with active inflammatory bowel disease is due to impeded protein folding. Biochem J 441:87–93

    PubMed  CAS  Google Scholar 

  69. Hodin CM, Verdam FJ, Grootjans J, Rensen SS, Verheyen FK, Dejong CH et al (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

    PubMed  CAS  Google Scholar 

  70. Maingat F, Halloran B, Acharjee S, van Marle G, Church D, Gill MJ et al (2011) Inflammation and epithelial cell injury in AIDS enteropathy: involvement of endoplasmic reticulum stress. FASEB J 25:2211–2220

    PubMed  CAS  Google Scholar 

  71. Grootjans J, Hodin CM, de Haan JJ, Derikx JP, Rouschop KM, Verheyen FK et al (2010) Level of activation of the unfolded protein response correlates with Paneth cell apoptosis in human small intestine exposed to ischemia-reperfusion. Gastroenterology 140:529–539

    Google Scholar 

  72. 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 491:119–124

    PubMed  CAS  Google Scholar 

  73. Randow F, Seed B (2001) Endoplasmic reticulum chaperone gp96 is required for innate immunity but not cell viability. Nat Cell Biol 3:891–896

    PubMed  CAS  Google Scholar 

  74. Rolhion N, Barnich N, Bringer MA, Glasser AL, Ranc J, Hebuterne X et al (2010) Abnormally expressed ER stress response chaperone Gp96 in CD favours adherent-invasive Escherichia coli invasion. Gut 59:1355–1362

    PubMed  CAS  Google Scholar 

  75. Darfeuille-Michaud A, Boudeau J, Bulois P, Neut C, Glasser AL, Barnich N et al (2004) High prevalence of adherent-invasive Escherichia coli associated with ileal mucosa in Crohn's disease. Gastroenterology 127:412–421

    PubMed  Google Scholar 

  76. Ozcan U, Cao Q, Yilmaz E, Lee AH, Iwakoshi NN, Ozdelen E et al (2004) Endoplasmic reticulum stress links obesity, insulin action, and type 2 diabetes. Science 306:457–461

    PubMed  Google Scholar 

  77. Sawada M, Takahashi K, Sawada S, Midorikawa O (1991) Selective killing of Paneth cells by intravenous administration of dithizone in rats. Int J Exp Pathol 72:407–421

    PubMed  CAS  Google Scholar 

  78. Kamat A, Ancuta P, Blumberg RS, Gabuzda D (2010) Serological markers for inflammatory bowel disease in AIDS patients with evidence of microbial translocation. PLoS One 5:e15533

    PubMed  Google Scholar 

  79. Wu X, Sun L, Zha W, Studer E, Gurley E, Chen L et al (2010) HIV protease inhibitors induce endoplasmic reticulum stress and disrupt barrier integrity in intestinal epithelial cells. Gastroenterology 138:197–209

    PubMed  CAS  Google Scholar 

  80. Zheng W, Rosenstiel P, Huse K, Sina C, Valentonyte R, Mah N et al (2006) Evaluation of AGR2 and AGR3 as candidate genes for inflammatory bowel disease. Genes Immun 7:11–18

    PubMed  CAS  Google Scholar 

  81. 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 40:955–962

    PubMed  CAS  Google Scholar 

  82. McGovern DP, Gardet A, Torkvist L, Goyette P, Essers J, Taylor KD et al (2010) Genome-wide association identifies multiple ulcerative colitis susceptibility loci. Nat Genet 42:332–337

    Google Scholar 

  83. Barrett JC, Clayton DG, Concannon P, Akolkar B, Cooper JD, Erlich HA et al (2009) Genome-wide association study and meta-analysis find that over 40 loci affect risk of type 1 diabetes. Nat Genet 41:703–707

    PubMed  CAS  Google Scholar 

  84. Moffatt MF, Gut IG, Demenais F, Strachan DP, Bouzigon E, Heath S et al (2010) A large-scale, consortium-based genomewide association study of asthma. N Engl J Med 363:1211–1221

    PubMed  CAS  Google Scholar 

  85. Moffatt MF, Kabesch M, Liang L, Dixon AL, Strachan D, Heath S et al (2007) Genetic variants regulating ORMDL3 expression contribute to the risk of childhood asthma. Nature 448:470–473

    PubMed  CAS  Google Scholar 

  86. Miller M, Tam AB, Cho JY, Doherty TA, Pham A, Khorram N et al (2012) ORMDL3 is an inducible lung epithelial gene regulating metalloproteases, chemokines, OAS, and ATF6. Proc Natl Acad Sci U S A 109:16648–16653

    PubMed  CAS  Google Scholar 

  87. Cantero-Recasens G, Fandos C, Rubio-Moscardo F, Valverde MA, Vicente R (2010) The asthma-associated ORMDL3 gene product regulates endoplasmic reticulum-mediated calcium signaling and cellular stress. Hum Mol Genet 19:111–121

    PubMed  CAS  Google Scholar 

  88. Wang Y, Shen J, Arenzana N, Tirasophon W, Kaufman RJ, Prywes R (2000) Activation of ATF6 and an ATF6 DNA binding site by the endoplasmic reticulum stress response. J Biol Chem 275:27013–27020

    PubMed  CAS  Google Scholar 

  89. Breslow DK, Collins SR, Bodenmiller B, Aebersold R, Simons K, Shevchenko A et al (2010) Orm family proteins mediate sphingolipid homeostasis. Nature 463:1048–1053

    PubMed  CAS  Google Scholar 

  90. Chatzikyriakidou A, Voulgari PV, Drosos AA (2011) What is the role of HLA-B27 in spondyloarthropathies? Autoimmun Rev 10:464–468

    PubMed  CAS  Google Scholar 

  91. Ozcan U, Yilmaz E, Ozcan L, Furuhashi M, Vaillancourt E, Smith RO et al (2006) Chemical chaperones reduce ER stress and restore glucose homeostasis in a mouse model of type 2 diabetes. Science 313:1137–1140

    PubMed  Google Scholar 

  92. Kars M, Yang L, Gregor MF, Mohammed BS, Pietka TA, Finck BN et al (2010) Tauroursodeoxycholic acid may improve liver and muscle but not adipose tissue insulin sensitivity in obese men and women. Diabetes 59:1899–1905

    PubMed  CAS  Google Scholar 

  93. Park SW and Ozcan U (2013) Potential for therapeutic manipulation of the UPR in disease. Semin Immunopathol 35. doi:10.1007/s00281-013-0370-z

  94. Berger E, Haller D (2011) Structure–function analysis of the tertiary bile acid TUDCA for the resolution of endoplasmic reticulum stress in intestinal epithelial cells. Biochem Biophys Res Commun 409:610–615

    PubMed  CAS  Google Scholar 

  95. Roma MG, Toledo FD, Boaglio AC, Basiglio CL, Crocenzi FA, Sanchez Pozzi EJ (2011) Ursodeoxycholic acid in cholestasis: linking action mechanisms to therapeutic applications. Clin Sci (Lond) 121:523–544

    CAS  Google Scholar 

  96. Paton AW, Beddoe T, Thorpe CM, Whisstock JC, Wilce MC, Rossjohn J et al (2006) AB5 subtilase cytotoxin inactivates the endoplasmic reticulum chaperone BiP. Nature 443:548–552

    PubMed  CAS  Google Scholar 

  97. Paton AW, Srimanote P, Talbot UM, Wang H, Paton JC (2004) A new family of potent AB(5) cytotoxins produced by Shiga toxigenic Escherichia coli. J Exp Med 200:35–46

    PubMed  CAS  Google Scholar 

  98. Paton AW, Voss E, Manning PA, Paton JC (1997) Shiga toxin-producing Escherichia coli isolates from cases of human disease show enhanced adherence to intestinal epithelial (Henle 407) cells. Infect Immun 65:3799–3805

    PubMed  CAS  Google Scholar 

  99. Futamura Y, Tashiro E, Hironiwa N, Kohno J, Nishio M, Shindo K et al (2007) Trierixin, a novel inhibitor of ER stress-induced XBP1 activation from Streptomyces sp. II. structure elucidation. J Antibiot (Tokyo) 60:582–585

    CAS  Google Scholar 

  100. Tashiro E, Hironiwa N, Kitagawa M, Futamura Y, Suzuki S, Nishio M et al (2007) Trierixin, a novel Inhibitor of ER stress-induced XBP1 activation from Streptomyces sp. 1. Taxonomy, fermentation, isolation and biological activities. J Antibiot (Tokyo) 60:547–553

    CAS  Google Scholar 

  101. Duboc H, Rajca S, Rainteau D, Benarous D, Maubert MA, Quervain E et al (2012) Connecting dysbiosis, bile-acid dysmetabolism and gut inflammation in inflammatory bowel diseases. Gut 62:531–539

    Google Scholar 

  102. Crespo I, San-Miguel B, Prause C, Marroni N, Cuevas MJ, Gonzalez-Gallego J et al (2012) Glutamine treatment attenuates endoplasmic reticulum stress and apoptosis in TNBS-induced colitis. PLoS One 7:e50407

    PubMed  CAS  Google Scholar 

  103. Werner T, Wagner SJ, Martinez I, Walter J, Chang JS, Clavel T et al (2011) Depletion of luminal iron alters the gut microbiota and prevents Crohn's disease-like ileitis. Gut 60:325–333

    PubMed  CAS  Google Scholar 

  104. Richardson CE, Kooistra T, Kim DH (2010) An essential role for XBP-1 in host protection against immune activation in C. elegans. Nature 463:1092–1095

    PubMed  CAS  Google Scholar 

  105. Kaser A, Blumberg RS (2010) Survive an innate immune response through XBP1. Cell Res 20:506–507

    PubMed  Google Scholar 

  106. Chang JS, Ocvirk S, Berger E, Kisling S, Binder U, Skerra A et al (2012) Endoplasmic reticulum stress response promotes cytotoxic phenotype of CD8alphabeta+ intraepithelial lymphocytes in a mouse model for Crohn's disease-like ileitis. J Immunol 189:1510–1520

    PubMed  CAS  Google Scholar 

  107. Rivas MA, Beaudoin M, Gardet A, Stevens C, Sharma Y, Zhang CK et al (2011) Deep resequencing of GWAS loci identifies independent rare variants associated with inflammatory bowel disease. Nat Genet 43:1066–1073

    PubMed  CAS  Google Scholar 

  108. Das B, Cash MN, Hand AR, Shivazad A, Grieshaber SS, Robinson B et al (2010) Tissue distribution of murine muc19/smgc gene products. J Histochem Cytochem 58:141–156

    PubMed  CAS  Google Scholar 

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Acknowledgments

Work in the authors' laboratories has been supported by the European Research Council under the European Community's Seventh Framework Programme (FP7/2007-2013) / ERC Grant agreement n° 260961; the National Institute for Health Research Cambridge Biomedical Research Centre; the Addenbrooke's Charitable Trust (all A.K.); NIH grants DK044319, DK051362, DK053056, DK088199, and the Harvard Digestive Diseases Center (HDDC) (DK0034854) (all R.S.B.)

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The author's declare that they have no conflict of interests.

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Authors and Affiliations

  1. Division of Gastroenterology and Hepatology, Department of Medicine, University of Cambridge, Addenbrooke’s Hospital, Level 5, Box 157, Cambridge, CB2 0QQ, UK

    Arthur Kaser & Timon Erik Adolph

  2. Division of Gastroenterology, Hepatology and Endoscopy, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Thorn 1405, 75 Francis St, Boston, MA, 02115, USA

    Richard S. Blumberg

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  1. Arthur Kaser
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  2. Timon Erik Adolph
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  3. Richard S. Blumberg
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Correspondence to Arthur Kaser or Richard S. Blumberg.

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This article is a contribution to the special issue on “The unfolded protein response in immune diseases”—Guest Editors: Richard Blumberg and Arthur Kaser

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Kaser, A., Adolph, T.E. & Blumberg, R.S. The unfolded protein response and gastrointestinal disease. Semin Immunopathol 35, 307–319 (2013). https://doi.org/10.1007/s00281-013-0377-5

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