NOD2 downregulates colonic inflammation by IRF4-mediated inhibition of K63-linked polyubiquitination of RICK and TRAF6.
NOD2 downregulates colonic inflammation by IRF4-mediated inhibition of K63-linked polyubiquitination of RICK and TRAF6.
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核苷酸结合寡聚化结构域2(NOD2)基因是克罗恩病(CD)的主要危险因素，其基因多态性可导致NOD2功能丧失。然而，这种功能丧失如何导致CD易感性增加的分子解释仍不清楚。在之前探索这一问题的研究中，我们报道了人树突状细胞中的NOD2被其配体胞浆二肽(MDP)激活，负向调节Toll样受体(TLR)介导的炎症反应。在这里，我们发现NOD2激活导致干扰素调节因子4(IRF4)表达增加，并与肿瘤坏死因子受体相关因子6(TRAF6)和受体相互作用丝氨酸-苏氨酸激酶(RICK)结合。然后，我们发现这种结合导致IRF4介导的抑制Lys63连接的TRAF6和RICK的多泛素化，从而下调NF-κB的激活。最后，我们证明，MDP或IRF4给药对小鼠实验性结肠炎的保护作用与IRF4介导的对结肠固有层单核细胞TRAF6和Rick的多泛素化的影响相似。因此，这些发现确定了NOD2介导的肠道菌群天然免疫反应的调节机制，可以解释NOD2基因多态性和由此导致的NOD2功能障碍与CD的关系。
It is well established that polymorphisms of the nucleotide-binding oligomerization domain 2 (NOD2) gene, a major risk factor in Crohn's disease (CD), lead to loss of NOD2 function. However, a molecular explanation of how such loss of function leads to increased susceptibility to CD has remained unclear. In a previous study exploring this question we reported that activation of NOD2 in human dendritic cells by its ligand, muramyl dipeptide (MDP) negatively regulates Toll-like receptor (TLR)-mediated inflammatory responses. Here we show that NOD2 activation results in increased interferon regulatory factor 4 (IRF4) expression and binding to TNF receptor associated factor 6 (TRAF6) and receptor interacting serine-threonine kinase (RICK). We then show that such binding leads to IRF4-mediated inhibition of Lys63-linked polyubiquitination of TRAF6 and RICK and thus to down-regulation of NF-κB activation. Finally, we demonstrate that protection of mice from the development of experimental colitis by MDP or IRF4 administration is accompanied by similar IRF4-mediated effects on polyubiquitination of TRAF6 and RICK in colonic lamina propria mononuclear cells. These findings thus define a mechanism of NOD2-mediated regulation of innate immune responses to intestinal microflora that could explain the relation of NOD2 polymorphisms and resultant NOD2 dysfunction to CD.
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DOI：
10.4049/jimmunol.0900582
发表时间：
2009-12-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
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作者：
Castellaneta A;Sumpter TL;Chen L;Tokita D;Thomson AW
通讯作者：
Thomson AW
影响因子：
32.4
作者：
Bertrand, Mathieu J. M.;Doiron, Karine;Saleh, Maya
通讯作者：
Saleh, Maya
影响因子：
15.9
作者：
Fichtner-Feigl, S;Fuss, IJ;Kitani, A
通讯作者：
Kitani, A
影响因子：
30.3
作者：
Meinzer, Ulrich;Barreau, Frederick;Hugot, Jean-Pierre
通讯作者：
Hugot, Jean-Pierre
影响因子：
8
作者：
通讯作者：
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