Crohn's disease: NOD2, autophagy and ER stress converge.
Polymorphisms in NOD2, encoding an intracellular pattern recognition receptor, contribute the largest fraction of genetic risk for Crohn's disease among the >40 risk loci identified so far. Autophagy plays a prominent role in the innate immune response towards intracellular bacteria. The discovery of the autophagy genes ATG16L1 and IRGM as risk factors for Crohn's disease turned autophagy into the spotlight in inflammatory bowel disease (IBD). Remarkably, NOD2 has recently been identified as a potent autophagy inducer. A physical interaction of NOD2 and ATG16L1 appears to be required for autophagic clearance of intracellular pathogens. Moreover, Crohn's disease-associated NOD2 and ATG16L1 variants exhibit a defect in the induction of an autophagic response and hence predict autophagy as a key converging mechanism that leads to Crohn's disease. Another pathway that is closely intertwined with autophagy and mutually cross-regulated is the unfolded protein response (UPR), which is induced by endoplasmic reticulum (ER) stress. Genes involved in the UPR (XBP1, ORMDL3) have also been genetically associated with Crohn's disease and ulcerative colitis. Moreover, the intestinal epithelium at the interface between host and microbe appears particularly affected by IBD-associated hypomorphic function of autophagy and the UPR. The functional convergence of main genetic risk factors for IBD on these innate immune pathways has hence important implications for the host's interaction with the microbiota. Moreover, the genetic convergence on these molecular mechanisms may open novel therapeutic options for IBD that deserve further exploration.
Department of Medicine II, Anichstr 35, A-6020 Innsbruck, Austria.
Teresa
T
Fritz
Lukas
L
Niederreiter
Timon
T
Adolph
Richard S
RS
Blumberg
Arthur
A
Kaser
D000818:Animals; D001343:Autophagy; D000071183:Autophagy-Related Proteins; D002352:Carrier Proteins / Q000235:genetics; D003424:Crohn Disease / Q000188:drug therapy / Q000235:genetics* / Q000503:physiopathology; D004268:DNA-Binding Proteins / Q000235:genetics; D059865:Endoplasmic Reticulum Stress / Q000235:genetics*; D005802:Genes, MHC Class II / Q000235:genetics; D014644:Genetic Variation; D006801:Humans; D054892:Metagenome / Q000502:physiology; D053473:Nod2 Signaling Adaptor Protein / Q000235:genetics*; D019879:Paneth Cells / Q000502:physiology; D020641:Polymorphism, Single Nucleotide; D000071701:Regulatory Factor X Transcription Factors; D015398:Signal Transduction / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics; D056811:Unfolded Protein Response / Q000235:genetics; D000071717:X-Box Binding Protein 1
C518959:ATG16L1 protein, human; D000071183:Autophagy-Related Proteins; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; C429018:NOD2 protein, human; D053473:Nod2 Signaling Adaptor Protein; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors; D000071717:X-Box Binding Protein 1; C000605543:XBP1 protein, human
J Clin Invest. 2001 Mar;107(5):585-93
11238559
Nature. 2010 Mar 4;464(7285):59-65
20203603
Nat Genet. 2008 Aug;40(8):955-62
18587394
N Engl J Med. 2009 Nov 19;361(21):2066-78
19923578
Int J Cell Biol. 2010;2010:930509
20145727
J Biol Chem. 2002 Nov 1;277(44):41701-5
12194982
Am J Physiol. 1997 May;272(5 Pt 1):G1249-57
9176237
Nature. 2008 Nov 13;456(7219):264-8
18849965
Annu Rev Genet. 2009;43:67-93
19653858
Science. 2004 Oct 15;306(5695):457-61
15486293
Nat Immunol. 2009 May;10(5):471-9
19349988
Cell Res. 2010 May;20(5):506-7
20436510
Proc Natl Acad Sci U S A. 2009 Sep 15;106(37):15813-8
19805227
Nature. 2008 Nov 13;456(7219):259-63
18849966
Immunol Rev. 2009 Jan;227(1):189-202
19120485
J Clin Invest. 1990 Sep;86(3):972-80
2168444
Clin Exp Immunol. 2004 Nov;138(2):323-9
15498044
Gut. 2008 Jun;57(6):717-20
18272545
Nature. 2006 Jul 6;442(7098):39-44
16823444
Gut. 2005 Nov;54(11):1515-8
16227353
Development. 2001 Apr;128(8):1443-55
11262243
Curr Biol. 2004 Dec 29;14(24):2217-27
15620648
Genes Dev. 2009 Oct 1;23(19):2294-306
19762508
Cell. 2007 Oct 5;131(1):33-45
17923086
J Biol Chem. 2006 Oct 6;281(40):30299-304
16901900
Clin Pharmacol Ther. 2007 Oct;82(4):381-8
17728765
Cell. 2008 Jan 11;132(1):27-42
18191218
Nature. 2001 May 31;411(6837):603-6
11385577
Cell. 2010 Mar 19;140(6):859-70
20303876
Autophagy. 2007 Mar-Apr;3(2):160-2
17204854
J Cell Biol. 2005 Sep 26;170(7):1101-11
16186256
PLoS Med. 2008 Mar 4;5(3):e54
18318598
Science. 2006 Aug 25;313(5790):1137-40
16931765
Nat Immunol. 2010 May;11(5):411-8
20351694
Proc Natl Acad Sci U S A. 2005 Dec 13;102(50):18129-34
16330776
Nat Genet. 2007 Feb;39(2):207-11
17200669
Gastroenterology. 1998 Dec;115(6):1405-13
9834268
Science. 2006 Sep 8;313(5792):1438-41
16888103
Immunity. 2007 Oct;27(4):549-59
17967410
J Immunol. 1995 Mar 1;154(5):2434-40
7868909
Annu Rev Biochem. 2005;74:739-89
15952902
J Exp Med. 2009 Aug 3;206(8):1709-16
19581406
Nature. 2001 May 31;411(6837):599-603
11385576
Annu Rev Genomics Hum Genet. 2009;10:89-116
19453248
J Clin Invest. 2010 Jan;120(1):127-41
20038797
Nat Immunol. 2009 Dec;10(12):1267-74
19881508
Gastroenterology. 2002 Jan;122(1):44-54
11781279
Cell. 2004 Dec 17;119(6):753-66
15607973
J Biol Chem. 2008 May 30;283(22):15370-80
18356160
PLoS One. 2008;3(10):e3391
18852889
Nat Genet. 2007 May;39(5):596-604
17435756
Proc Natl Acad Sci U S A. 2007 Dec 4;104(49):19440-5
18032608
Nat Genet. 2004 Jun;36(6):585-95
15146184
Hum Mol Genet. 2010 Jan 1;19(1):111-21
19819884
Nat Med. 2010 Apr;16(4):438-45
20348923
Am J Pathol. 2007 Aug;171(2):513-24
17620365
Nat Cell Biol. 2009 Dec;11(12):1473-80
19855386
Proc Natl Acad Sci U S A. 2007 Nov 27;104(48):19023-8
18024584
Cell. 2010 Jun 25;141(7):1135-45
20602997
Annu Rev Immunol. 2010;28:573-621
20192811
Science. 2005 Feb 4;307(5710):734-8
15692052
Mol Cell. 2007 Jan 26;25(2):193-205
17244528
Nat Genet. 2009 Jan;41(1):71-6
19098911
Cell. 2008 Sep 5;134(5):743-56
18775308
Nat Genet. 2010 Apr;42(4):332-7
20228799
Nat Immunol. 2009 Oct;10(10):1073-80
19701189
Cell Microbiol. 2010 Jan;12(1):99-113
19747213
Cell Metab. 2010 Jun 9;11(6):467-78
20519119
Mol Cell. 2008 Mar 14;29(5):541-51
18342602
Nat Rev Cancer. 2004 May;4(5):335-48
15122205
Am J Hum Genet. 2002 Apr;70(4):845-57
11875755
Nature. 2007 Jun 7;447(7145):661-78
17554300
Nature. 2007 Oct 18;449(7164):851-61
17943122
Nature. 2010 Feb 25;463(7284):1092-5
20182512
Nat Genet. 2007 Jul;39(7):830-2
17554261
Nat Genet. 2008 Sep;40(9):1107-12
19165925
J Biol Chem. 2010 Apr 9;285(15):11061-7
20147746
Proc Natl Acad Sci U S A. 2007 Aug 21;104(34):13780-5
17699621
Nat Rev Drug Discov. 2007 Apr;6(4):304-12
17396135
Gut. 2008 Sep;57(9):1294-6
18719139
FEBS Lett. 2010 Apr 2;584(7):1287-95
20083114
Gastroenterology. 2004 Aug;127(2):412-21
15300573
Cell Death Differ. 2007 Feb;14(2):230-9
16794605
Nat Immunol. 2004 Aug;5(8):800-8
15220916
Lancet. 2001 Jun 16;357(9272):1925-8
11425413
Nat Immunol. 2010 Jan;11(1):55-62
19898471
Cell. 2005 Jan 28;120(2):237-48
15680329
Nat Med. 2010 Apr;16(4):429-37
20348926
Nat Med. 2010 Jan;16(1):90-7
19966812
Hum Mol Genet. 2007 Mar 15;16(6):618-29
17331981
Science. 2010 Jul 9;329(5988):229-32
20522742
Mol Cell Biol. 2006 Dec;26(24):9220-31
17030611
PLoS Biol. 2010 Jan 26;8(1):e1000294
20126254
Science. 2005 Feb 4;307(5710):731-4
15692051
Proc Natl Acad Sci U S A. 2001 Nov 6;98(23):13249-54
11606779
Mucosal Immunol. 2010 Jan;3(1):11-6
19865077
Am J Gastroenterol. 2008 Sep;103(9):2284-92
18671816
Semin Immunol. 2009 Jun;21(3):156-63
19237300
Nat Rev Immunol. 2008 Sep;8(9):663-74
18670423