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首页> 外文期刊>Nature immunology >The signaling adaptor TRAF1 negatively regulates Toll-like receptor signaling and this underlies its role in rheumatic disease
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The signaling adaptor TRAF1 negatively regulates Toll-like receptor signaling and this underlies its role in rheumatic disease

机译:信令适配器Traf1负调节Toll样受体信号传导,这使其在风湿病中的作用下降

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TRAF1 is a signaling adaptor known for its role in tumor necrosis factor receptor-induced cell survival. Here we show that monocytes from healthy human subjects with a rheumatoid arthritis-associated single-nucleotide polymorphism (SNP) in the TRAF1 gene express less TRAF1 protein but greater amounts of inflammatory cytokines in response to lipopolysaccharide (LPS). The TRAF1 MATH domain binds directly to three components of the linear ubiquitination (LUBAC) complex, SHARPIN, HOIP and HOIL-1, to interfere with the recruitment and linear ubiquitination of NEMO. This results in decreased NF-KB activation and cytokine production, independently of tumor necrosis factor. Consistent with this, Traf1(-/-) mice show increased susceptibility to LPS-induced septic shock. These findings reveal an unexpected role for TRAF1 in negatively regulating Toll-like receptor signaling, providing a mechanistic explanation for the increased inflammation seen with a disease-associated TRAF1 SNP.
机译:TRAF1是一种以其在肿瘤坏死因子受体诱导的细胞存活中的作用而已知的信号衔接子。 在这里,我们表明,在TRAF1基因中具有类风湿性关节炎相关的单核苷酸多态性(SNP)的单核细胞表达较少的TRAF1蛋白,但响应于脂多糖(LPS),较多的炎性细胞因子。 TRAF1数学域直接与线性泛素(Lubac)复合物,Sharpin,Hoip和Hoot-1的三个组分绑定,以干扰Nemo的招生和线性泛酸。 这导致NF-KB活化和细胞因子产生降低,独立于肿瘤坏死因子。 符合此,TRAF1( - / - )小鼠显示对LPS引起的脓毒症休克的易感性增加。 这些发现揭示了TRAF1在负面调节的Toll样受体信号传导中的意外作用,为疾病相关的TRAF1 SNP的增加的炎症提供机械解释。

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