Sharpin prevents skin inflammation by inhibiting TNFR1-induced keratinocyte apoptosis.
Sharpin prevents skin inflammation by inhibiting TNFR1-induced keratinocyte apoptosis.
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DOI：
10.7554/elife.03422
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发表时间：
2014-12-02
期刊：
影响因子：
7.7
通讯作者：
Ikeda F
中科院分区：
文献类型：
--
作者：
Kumari S;Redouane Y;Lopez-Mosqueda J;Shiraishi R;Romanowska M;Lutzmayer S;Kuiper J;Martinez C;Dikic I;Pasparakis M;Ikeda F
线性泛素链组装复合物（LUBAC）是产生线性泛素链的E3连接酶复合物，并且对于肿瘤坏死因子（TNF）信号传导激活是重要的。缺乏Sharpin（LUBAC的一个关键亚基）的小鼠会自发地在皮肤和其他器官中产生炎性病变。在这里，我们表明，TNF受体1（TNFR 1）相关的死亡结构域（TRADD）依赖性TNFR 1信号在表皮角质形成细胞驱动皮肤炎症Sharpin缺陷小鼠。Fas相关蛋白与死亡结构域（FADD）结合受体相互作用蛋白激酶3（RIPK 3）缺陷的表皮限制性消融完全预防了皮肤炎症，而单一RIPK 3缺陷仅延迟和部分改善Sharpin缺陷小鼠中的病变发展，表明炎症主要由TRADD和FADD依赖性角质形成细胞凋亡驱动，而坏死性凋亡起次要作用。在细胞水平上，Sharpin缺乏致敏原代鼠角质形成细胞，人角质形成细胞，和小鼠胚胎成纤维细胞TNF诱导的细胞凋亡。Sharpin缺陷HaCaT细胞中FADD或TRADD的耗尽抑制TNF诱导的细胞凋亡，表明FADD和TRADD在角质形成细胞中Sharpin依赖性抗细胞凋亡信号传导中的重要性。DOI：http://dx.doi.org/10.7554/eLife.03422.001在对受伤或感染的反应中，身体的某些部位可能会发炎，因为免疫系统试图修复损伤和/或破坏进入体内的任何微生物或毒素。在单个细胞的水平上，炎症可能涉及细胞以两种方式之一死亡：凋亡和坏死性凋亡。细胞凋亡是一个高度受控的过程，在此过程中，细胞的内容物被安全地破坏，以防止对周围细胞的损害。另一方面，坏死是不受控制的：细胞破裂并将其内容物释放到周围环境中。炎症是由一种叫做TNF的蛋白质激活的，TNF是由一种复合物控制的，其中包括一种叫做Sharpin的蛋白质。缺乏Sharpin蛋白的小鼠即使没有受伤或感染，也会在皮肤和其他器官上产生炎症。然而，尚不清楚Sharpin蛋白如何控制TNF以预防炎症。Kumari等人发现，缺乏Sharpin的小鼠的炎症取决于TNF与另一种称为TRADD的蛋白质的相互作用。实验还表明，炎症主要由细胞凋亡驱动，坏死性凋亡仅起次要作用。在哺乳动物细胞中进行的进一步实验表明，TRADD和另一种蛋白质（称为FADD）与Sharpin一起防止细胞凋亡。在分子水平上，Sharpin可以诱导一种特殊类型的蛋白质修饰（称为线性泛素化），因此下一个挑战是准确地找出Sharpin如何使用这个过程来防止细胞凋亡。DOI：http://dx.doi.org/10.7554/eLife.03422.002网站
Linear Ubiquitin chain Assembly Complex (LUBAC) is an E3 ligase complex that generates linear ubiquitin chains and is important for tumour necrosis factor (TNF) signaling activation. Mice lacking Sharpin, a critical subunit of LUBAC, spontaneously develop inflammatory lesions in the skin and other organs. Here we show that TNF receptor 1 (TNFR1)-associated death domain (TRADD)-dependent TNFR1 signaling in epidermal keratinocytes drives skin inflammation in Sharpin-deficient mice. Epidermis-restricted ablation of Fas-associated protein with death domain (FADD) combined with receptor-interacting protein kinase 3 (RIPK3) deficiency fully prevented skin inflammation, while single RIPK3 deficiency only delayed and partly ameliorated lesion development in Sharpin-deficient mice, showing that inflammation is primarily driven by TRADD- and FADD-dependent keratinocyte apoptosis while necroptosis plays a minor role. At the cellular level, Sharpin deficiency sensitized primary murine keratinocytes, human keratinocytes, and mouse embryonic fibroblasts to TNF-induced apoptosis. Depletion of FADD or TRADD in Sharpin-deficient HaCaT cells suppressed TNF-induced apoptosis, indicating the importance of FADD and TRADD in Sharpin-dependent anti-apoptosis signaling in keratinocytes. DOI: http://dx.doi.org/10.7554/eLife.03422.001 In response to an injury or an infection, areas of the body can become inflamed as the immune system attempts to repair the damage and/or destroy any microbes or toxins that have entered the body. At the level of individual cells inflammation can involve cells being programmed to die in one of two ways: apoptosis and necroptosis. Apoptosis is a highly controlled process during which the contents of the cell are safely destroyed in order to prevent damage to surrounding cells. Necroptosis, on the other hand, is not controlled: the cell bursts and releases its contents into the surroundings. Inflammation is activated by a protein called TNF, which is controlled by a complex that includes a protein called Sharpin. Mice that lack the Sharpin protein develop inflammation on the skin and other organs, even in the absence of injury or infection. However, it is not clear how the Sharpin protein controls TNF to prevent inflammation. Kumari et al. have found that inflammation in mice lacking Sharpin depends on TNF interacting with another protein called TRADD. The experiments also show that the inflammation is mainly driven by apoptosis, with necroptosis having only a minor role. Further experiments carried out in mammal cells showed that TRADD and another protein (called FADD) work with Sharpin to prevent apoptosis. At the molecular level, Sharpin is known to induce a special type of protein modification (called linear ubiquitination) with two partner proteins, so the next challenge is to work out exactly how Sharpin uses this process to prevent apoptosis. DOI: http://dx.doi.org/10.7554/eLife.03422.002