SHARPIN forms a linear ubiquitin ligase complex regulating NF-κB activity and apoptosis.
SHARPIN forms a linear ubiquitin ligase complex regulating NF-κB activity and apoptosis.
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DOI：
10.1038/nature09814
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发表时间：
2011-03-31
期刊：
影响因子：
64.8
通讯作者：
Dikic, Ivan
中科院分区：
文献类型：
--
作者：
Ikeda, Fumiyo;Deribe, Yonathan Lissanu;Skanland, Sigrid S.;Stieglitz, Benjamin;Grabbe, Caroline;Franz-Wachtel, Mirita;van Wijk, Sjoerd J. L.;Goswami, Panchali;Nagy, Vanja;Terzic, Janos;Tokunaga, Fuminori;Androulidaki, Ariadne;Nakagawa, Tomoko;Pasparakis, Manolis;Iwai, Kazuhiro;Sundberg, John P.;Schaefer, Liliana;Rittinger, Katrin;Macek, Boris;Dikic, Ivan
Sharpin是一种泛素结合和泛素样结构域的蛋白质，当在小鼠身上发生突变时，会导致免疫系统紊乱和多器官炎症。在此，我们报道了夏尔平作为线性泛素链组装复合体(LUBAC)的一个新成分的功能，以及夏尔平的缺失导致了NF-κB和凋亡信号通路的失调，解释了夏尔平缺陷小鼠慢性增生性皮炎表现出的严重表型。当与LUBAC亚基HOIP结合后，Sharpin在体外和体内刺激线性泛素链的形成。夏尔平和HOIP的共表达促进IκB激酶(IKK)的接头NEMO的线性泛素化和随后的NF-κB信号的激活，而夏尔平缺乏会导致B细胞、巨噬细胞和小鼠胚胎成纤维细胞(MEF)中IKK复合体和NF-κB的激活受损。当同时下调HOIL-1L时，这种效应进一步增强。HOIL-1L是LUBAC的另一个HOIP结合成分。此外，夏普林缺乏通过依赖FADD和Caspase8的途径在肿瘤坏死因子α刺激下导致细胞迅速死亡。因此，夏尔平在体内通过不同的途径激活NF-κB并抑制细胞凋亡。
SHARPIN is a ubiquitin-binding and ubiquitin-like domain-containing protein which, when mutated in mice, results in immune system disorders and multiorgan inflammation. Here we report that SHARPIN functions as a novel component of the Linear Ubiquitin Chain Assembly Complex (LUBAC) and that the absence of SHARPIN causes disregulation of NF-κB and apoptotic signalling pathways, explaining the severe phenotypes displayed by chronic proliferative dermatitis in SHARPIN deficient mice. Upon binding to the LUBAC subunit HOIP, SHARPIN stimulates the formation of linear ubiquitin chains in vitro and in vivo. Co-expression of SHARPIN and HOIP promotes linear ubiquitylation of NEMO, an adaptor of the IκB kinases (IKKs) and subsequent activation of NF-κB signalling, while SHARPIN deficiency in mice causes an impaired activation of the IKK complex and NF-κB in B cells, macrophages, and mouse embryonic fibroblasts (MEFs). This effect is further enhanced upon concurrent downregulation of HOIL-1L, another HOIP-binding component of LUBAC. In addition, SHARPIN deficiency leads to rapid cell death upon TNFα stimulation via FADD- and Caspase-8-dependent pathways. SHARPIN thus activates NF-κB and inhibits apoptosis via distinct pathways in vivo.
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影响因子：
5
作者：
Seymour, R. E.;Hasham, M. G.;Sundberg, J. P.
通讯作者：
Sundberg, J. P.
影响因子：
14.8
作者：
Rappsilber, Juri;Mann, Matthias;Ishihama, Yasushi
通讯作者：
Ishihama, Yasushi
影响因子：
64.5
作者：
Micheau, O;Tschopp, J
通讯作者：
Tschopp, J
影响因子：
1
作者：
GIJBELS, MJJ;HOGENESCH, H;ZURCHER, C
通讯作者：
ZURCHER, C
影响因子：
7
作者：
Olsen, JV;de Godoy, LMF;Mann, M
通讯作者：
Mann, M