NOD1 contributes to mouse host defense against Helicobacter pylori via induction of type I IFN and activation of the ISGF3 signaling pathway.
Nucleotide-binding oligomerization domain 1 (NOD1) is an intracellular epithelial cell protein known to play a role in host defense at mucosal surfaces. Here we show that a ligand specific for NOD1, a peptide derived from peptidoglycan, initiates an unexpected signaling pathway in human epithelial cell lines that results in the production of type I IFN. Detailed analysis revealed the components of the signaling pathway. NOD1 binding to its ligand triggered activation of the serine-threonine kinase RICK, which was then able to bind TNF receptor-associated factor 3 (TRAF3). This in turn led to activation of TANK-binding kinase 1 (TBK1) and IkappaB kinase epsilon (IKKepsilon) and the subsequent activation of IFN regulatory factor 7 (IRF7). IRF7 induced IFN-beta production, which led to activation of a heterotrimeric transcription factor complex known as IFN-stimulated gene factor 3 (ISGF3) and the subsequent production of CXCL10 and additional type I IFN. In vivo studies showed that mice lacking the receptor for IFN-beta or subjected to gene silencing of the ISGF3 component Stat1 exhibited decreased CXCL10 responses and increased susceptibility to Helicobacter pylori infection, phenotypes observed in NOD1-deficient mice. These studies thus establish that NOD1 can activate the ISGF3 signaling pathway that is usually associated with protection against viral infection to provide mice with robust type I IFN-mediated protection from H. pylori and possibly other mucosal infections.
Watanabe
Tomohiro
T
Mucosal Immunity Section, Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, Maryland 20892, USA. tmhrwtnb@kuhp.kyoto-u.ac.jp
Asano
Naoki
N
Fichtner-Feigl
Stefan
S
Gorelick
Peter L
PL
Tsuji
Yoshihisa
Y
Matsumoto
Yuko
Y
Chiba
Tsutomu
T
Fuss
Ivan J
IJ
Kitani
Atsushi
A
Strober
Warren
W
D000818:Animals; D018925:Chemokines / Q000378:metabolism; D005260:Female; D016481:Helicobacter Infections / Q000378:metabolism*; D016480:Helicobacter pylori / Q000378:metabolism*; D006801:Humans; D007370:Interferon Type I / Q000378:metabolism*; D050832:Interferon-Stimulated Gene Factor 3 / Q000378:metabolism*; D050834:Interferon-Stimulated Gene Factor 3, gamma Subunit / Q000378:metabolism*; D008024:Ligands; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D053474:Nod1 Signaling Adaptor Protein / Q000378:metabolism*; D010455:Peptides / Q000737:chemistry; D011485:Protein Binding; D015398:Signal Transduction; D018417:Th1 Cells / Q000166:cytology
D018925:Chemokines; C494227:IRF9 protein, human; D007370:Interferon Type I; D050832:Interferon-Stimulated Gene Factor 3; D050834:Interferon-Stimulated Gene Factor 3, gamma Subunit; D008024:Ligands; C119067:NOD1 protein, human; D053474:Nod1 Signaling Adaptor Protein; C507873:Nod1 protein, mouse; D010455:Peptides
Nature. 2002 Mar 14;416(6877):194-9
11894098
J Immunol. 1998 Nov 1;161(9):4736-44
9794404
Proc Natl Acad Sci U S A. 2007 Apr 17;104(16):6764-9
17420470
Clin Exp Immunol. 2000 Nov;122(2):192-9
11091274
Immunity. 2004 Nov;21(5):719-31
15539157
Nat Immunol. 2006 Jan;7(1):40-8
16286919
Immunity. 2007 Apr;26(4):445-59
17433730
PLoS Pathog. 2008 Nov;4(11):e1000228
19043560
J Biol Chem. 2005 Nov 4;280(44):36714-8
16150702
Mol Immunol. 2005 May;42(8):879-85
15829277
Curr Opin Immunol. 2002 Feb;14(1):111-6
11790540
N Engl J Med. 2001 Sep 13;345(11):784-9
11556297
Nat Immunol. 2003 Jul;4(7):702-7
12796777
J Clin Invest. 2005 Nov;115(11):3057-71
16239967
J Immunol. 2000 Jun 15;164(12):6503-8
10843708
Gut. 2005 Nov;54(11):1515-8
16227353
Infect Immun. 2003 Jun;71(6):3628-33
12761151
J Biol Chem. 2003 Aug 29;278(35):32962-8
12813035
Nature. 2006 Jan 12;439(7073):208-11
16306936
J Biol Chem. 2006 Oct 13;281(41):31119-30
16912041
Gastroenterology. 2002 Dec;123(6):1949-61
12454852
Gastroenterology. 2000 Apr;118(4):749-59
10734026
Proc Natl Acad Sci U S A. 2005 Jun 28;102(26):9247-52
15956202
Nat Med. 2007 Apr;13(4):470-6
17401375
Annu Rev Pathol. 2009;4:365-98
18928408
J Clin Invest. 2008 Feb;118(2):545-59
18188453
J Clin Invest. 2006 Apr;116(4):1092-101
16543949
Autoimmunity. 2004 Aug;37(5):273-82
15672495
J Immunol. 2006 Mar 15;176(6):3796-803
16517750
Infect Immun. 2004 Mar;72(3):1487-95
14977954
Nature. 2006 Jan 12;439(7073):204-7
16306937
Cell Death Differ. 2007 Apr;14(4):830-9
17186025
Biochem Biophys Res Commun. 2005 Apr 15;329(3):1139-46
15752772
J Gastroenterol. 1999 Oct;34(5):560-70
10535482
Nat Rev Immunol. 2005 Sep;5(9):675-87
16110316
J Biol Chem. 1998 Jul 3;273(27):16968-75
9642260
Proc Natl Acad Sci U S A. 1996 Apr 16;93(8):3613-8
8622984
Nat Rev Mol Cell Biol. 2001 May;2(5):378-86
11331912
J Exp Med. 2005 May 2;201(9):1435-46
15851485
Mol Cell Biochem. 2005 Jan;268(1-2):129-40
15724446
J Immunol. 2007 Jul 1;179(1):514-21
17579072
J Biol Chem. 2000 Sep 8;275(36):27823-31
10880512
Circ Res. 2005 Feb 18;96(3):319-26
15653568
Gut. 2003 Nov;52(11):1591-7
14570728
J Immunol. 1998 Mar 1;160(5):2188-96
9498757
J Biol Chem. 2003 Nov 21;278(47):46565-75
12968033
Annu Rev Biochem. 2005;74:355-83
15952891
Nat Genet. 2003 Mar;33(3):388-91
12590259
Nat Rev Immunol. 2006 Jan;6(1):9-20
16493424
Proc Natl Acad Sci U S A. 2008 Mar 4;105(9):3503-8
18292232
Nat Immunol. 2004 Nov;5(11):1166-74
15489856
Science. 1994 Jun 24;264(5167):1918-21
8009221
J Exp Med. 2006 Jan 23;203(1):203-13
16418393
FEBS Lett. 1997 May 5;407(3):313-9
9175875
Nat Immunol. 2004 Aug;5(8):800-8
15220916
J Immunol. 1997 Jan 15;158(2):962-7
8993017
J Clin Invest. 2005 Mar;115(3):695-702
15765149
J Biol Chem. 2007 Dec 14;282(50):36223-9
17947236
EMBO Rep. 2001 Aug;2(8):736-42
11463746
Nat Rev Immunol. 2003 May;3(5):371-82
12766759
Virology. 2006 Feb 5;345(1):96-104
16253303