A Crohn's disease-associated NOD2 mutation suppresses transcription of human IL10 by inhibiting activity of the nuclear ribonucleoprotein hnRNP-A1.
A Crohn's disease-associated NOD2 mutation suppresses transcription of human IL10 by inhibiting activity of the nuclear ribonucleoprotein hnRNP-A1.
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编码细胞质传感器Nod 2的基因中的常见突变，涉及在核苷酸3020（3020 insC）处的移码插入，与克罗恩病密切相关。3020 insC如何导致这种疾病是一个有争议的问题。临床研究已经确定，在具有3020 insC突变的克罗恩病患者中，白细胞介素10（IL-10）的产生缺陷，这表明3020 insC可能是一种功能缺失突变。然而，在这里我们发现3020 insC Nod 2突变蛋白积极抑制IL 10转录。3020 insC Nod 2突变体通过丝裂原活化蛋白激酶p38阻断核核糖核蛋白hnRNP-A1的磷酸化来抑制IL 10的转录。我们证实了克罗恩病患者外周血单个核细胞中hnRNP-A1磷酸化和hnRNP-A1与IL-10位点结合的损伤，这些患者携带3020 insC突变并且具有较低的IL-10产生。
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.
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