SHARPIN is a component of the NF-κB-activating linear ubiquitin chain assembly complex
SHARPIN is a component of the NF-κB-activating linear ubiquitin chain assembly complex
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DOI：
10.1038/nature09815
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发表时间：
2011-03-31
期刊：
影响因子：
64.8
通讯作者：
Iwai, Kazuhiro
中科院分区：
文献类型：
--
作者：
Tokunaga, Fuminori;Nakagawa, Tomoko;Iwai, Kazuhiro
Cpdm（慢性增殖性皮炎）小鼠会出现慢性皮炎和免疫缺陷，血清 IgM 增加 (1-3)，其症状类似于 X 连锁高 IgM 综合征和缺水性外胚层发育不良 (XHM-ED) 患者的症状，这是由 NEMO（NF-κ B 必需调节剂；也称为 IKBKG）突变引起的(4-6)。 Sharpin（突触后密度中 SHANK 相关 RH 结构域相互作用蛋白）(7) 基因的自发无效突变是小鼠中 cpdm 表型的原因(8)。 SHARPIN 与 HOIL-1L（也称为 RBCK1）(8,9) 显着相似，HOIL-1L 是线性泛素链组装复合物 (LUBAC) 的一个组成部分，后者通过线性多泛素链与 NEMO10-13 的缀合来诱导 NF-kappa B 激活。在这里，我们将 SHARPIN 确定为 LUBAC 的附加组件。含有SHARPIN的复合物可以线性泛素化NEMO和激活的NF-kappa B。因此，我们将LUBAC重新定义为含有SHARPIN、HOIL-1L和HOIP（也称为RNF31）的复合物。 SHARPIN 的缺失大大减少了 LUBAC 的量，从而导致小鼠胚胎成纤维细胞 (MEF) 或来自 cpdm 小鼠的 B 细胞中 TNF-α 和 CD40 介导的 NF-κ B 激活减弱。考虑到 cpdm 小鼠的多形性表型，这些结果证实了 LUBAC 介导的线性多泛素化在各种刺激诱导的 NF-κ B 激活中的预测作用，并强烈表明 LUBAC 诱导的 NF-κ B 激活参与各种疾病。
Cpdm (chronic proliferative dermatitis) mice develop chronic dermatitis and an immunodeficiency with increased serum IgM(1-3), symptoms that resemble those of patients with X-linked hyper-IgM syndrome and hypohydrotic ectodermal dysplasia (XHM-ED), which is caused by mutations in NEMO (NF-kappa B essential modulator; also known as IKBKG)(4-6). Spontaneous null mutations in the Sharpin (SHANK-associated RH domain interacting protein in postsynaptic density)(7) gene are responsible for the cpdm phenotype in mice(8). SHARPIN shows significant similarity to HOIL-1L (also known as RBCK1)(8,9), a component of linear ubiquitin chain assembly complex (LUBAC), which induces NF-kappa B activation through conjugation of linear polyubiquitin chains to NEMO10-13. Here, we identify SHARPIN as an additional component of LUBAC. SHARPIN-containing complexes can linearly ubiquitinate NEMO and activated NF-kappa B. Thus, we re-define LUBAC as a complex containing SHARPIN, HOIL-1L, and HOIP (also known as RNF31). Deletion of SHARPIN drastically reduced the amount of LUBAC, which resulted in attenuated TNF-alpha- and CD40-mediated activation of NF-kappa B in mouse embryonic fibroblasts (MEFs) or B cells from cpdm mice. Considering the pleomorphic phenotype of cpdm mice, these results confirm the predicted role of LUBAC-mediated linear polyubiquitination in NF-kappa B activation induced by various stimuli, and strongly suggest the involvement of LUBAC-induced NF-kappa B activation in various disorders.