Sharpin contributes to TNFα dependent NFκB activation and anti-apoptotic signalling in hepatocytes.
Sharpin contributes to TNFα dependent NFκB activation and anti-apoptotic signalling in hepatocytes.
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DOI：
10.1371/journal.pone.0029993
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Kreienkamp HJ
中科院分区：
文献类型：
--
作者：
Sieber S;Lange N;Kollmorgen G;Erhardt A;Quaas A;Gontarewicz A;Sass G;Tiegs G;Kreienkamp HJ
TNFα刺激肝细胞的促凋亡和抗凋亡信号。抗凋亡信号依赖于导致NFκB激活的泛素化级联反应。在Sharpin缺失的小鼠中，我们发现泛素结合蛋白Sharpin与一种产生线性泛素链的E3连接酶Hoip相互作用。sharpin缺乏使肝细胞对TNFα诱导的凋亡敏感，即使在没有转录抑制的情况下。在sharpin缺失小鼠肝细胞中，TNFα诱导的nf - κ b活化明显降低，这是由于TNFα磷酸化和降解的减少和延迟。注射tnf α诱导的脂多糖可严重加重sharpin缺乏小鼠的肝损伤和过早死亡。我们的研究结果表明，Sharpin在线性泛素链形成、NFκB激活和保护肝脏免受炎症损伤信号的保护中发挥了重要作用。
TNFα stimulates both pro- and anti-apoptotic signalling in hepatocytes. Anti-apoptotic signalling depends on a cascade of ubiquitylation steps leading to NFκB activation. Using Sharpin-deficient mice, we show that the ubiquitin binding protein Sharpin interacts with Hoip, an E3 ligase which generates linear ubiquitin chains. Sharpin-deficiency sensitized hepatocytes to induction of apoptosis by TNFα even in the absence of transcriptional inhibition. TNFα induced activation of NFκB was strongly reduced in hepatocytes from Sharpin-deficient mice, due to reduced and delayed phosphorylation and degradation of IκBα. Injection of TNFα-inducing lipopolysaccharides led to strongly exacerbated liver damage and premature death in Sharpin-deficient mice. Our findings point to an essential role of Sharpin in linear ubiquitin chain formation, NFκB activation, and protection of the liver against inflammatory damaging signals.
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影响因子：
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作者：
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通讯作者：
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