A Crohn's disease-associated NOD2 mutation suppresses transcription of human IL10 by inhibiting activity of the nuclear ribonucleoprotein hnRNP-A1.
A common mutation in the gene encoding the cytoplasmic sensor Nod2, involving a frameshift insertion at nucleotide 3020 (3020insC), is strongly associated with Crohn's disease. How 3020insC contributes to this disease is a controversial issue. Clinical studies have identified defective production of interleukin 10 (IL-10) in patients with Crohn's disease who bear the 3020insC mutation, which suggests that 3020insC may be a loss-of-function mutation. However, here we found that 3020insC Nod2 mutant protein actively inhibited IL10 transcription. The 3020insC Nod2 mutant suppressed IL10 transcription by blocking phosphorylation of the nuclear ribonucleoprotein hnRNP-A1 via the mitogen-activated protein kinase p38. We confirmed impairment in phosphorylation of hnRNP-A1 and binding of hnRNP-A1 to the IL10 locus in peripheral blood mononuclear cells from patients with Crohn's disease who bear the 3020insC mutation and have lower production of IL-10.
Department of Surgery II, Tokyo Women's Medical University, Tokyo, Japan.
Eiichiro
E
Noguchi
Yoichiro
Y
Homma
Xiaoyan
X
Kang
Mihai G
MG
Netea
Xiaojing
X
Ma
D000328:Adult; D000818:Animals; D003424:Crohn Disease / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease; D000076245:Heterogeneous Nuclear Ribonucleoprotein A1; D034481:Heterogeneous-Nuclear Ribonucleoprotein Group A-B / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D016753:Interleukin-10 / Q000096:biosynthesis* / Q000235:genetics; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009000:Monocytes / Q000276:immunology / Q000378:metabolism; D009154:Mutation; D053473:Nod2 Signaling Adaptor Protein / Q000235:genetics*; D014158:Transcription, Genetic
D000076245:Heterogeneous Nuclear Ribonucleoprotein A1; D034481:Heterogeneous-Nuclear Ribonucleoprotein Group A-B; C429018:NOD2 protein, human; D053473:Nod2 Signaling Adaptor Protein; D016753:Interleukin-10