Epstein-Barr virus encoded latent membrane protein 1 suppresses necroptosis through targeting RIPK1/3 ubiquitination.
Epstein-Barr virus encoded latent membrane protein 1 suppresses necroptosis through targeting RIPK1/3 ubiquitination.
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Epstein-Barr 病毒编码的潜伏膜蛋白 1 通过靶向 RIPK1/3 泛素化来抑制坏死性凋亡。
DOI：
10.1038/s41419-017-0081-9
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发表时间：
2018-01-19
影响因子：
9
通讯作者：
Cao Y
中科院分区：
文献类型：
--
作者：
Liu X;Li Y;Peng S;Yu X;Li W;Shi F;Luo X;Tang M;Tan Z;Bode AM;Cao Y
坏死性凋亡是一种替代的程序性细胞死亡途径，其在不存在细胞凋亡的情况下释放，并由含有受体介导蛋白激酶1（RIPK 1）和RIPK 3的信号复合物介导。这种形式的细胞死亡最近被牵连在宿主防御系统，以消除病原体感染的细胞。然而，只有少数病毒物种，如单纯疱疹病毒（HSV）和巨细胞病毒（CMV）已经进化出抑制坏死性凋亡的机制，以克服宿主的抗病毒防御，这是重要的成功发病机制。在这里，我们表明，γ-疱疹病毒EB病毒（EBV）阻断EBV感染的人鼻咽上皮细胞和鼻咽癌细胞的坏死性凋亡。我们的研究结果表明，EB病毒编码的潜伏膜蛋白1（LMP 1），它缺乏RIP同型相互作用基序（RHIM）域，有不同的机制从RHIM信号竞争，以抑制这种坏死性凋亡途径。有趣的是，LMP 1通过其C-末端激活区直接与RIPK 1和RIPK 3相互作用。更重要的是，LMP 1可以调节两种受体相互作用蛋白的翻译后修饰。然后，我们表明，LMP 1介导的促进K63-多聚泛素化RIPK 1，抑制RIPK 1蛋白表达和抑制K63-多聚泛素化RIPK 3诱导细胞命运从坏死性死亡到存活的转换。这些发现为EBV抑制坏死性凋亡提供了直接证据，并定义了LMP 1在坏死体形成之前中断坏死性凋亡起始过程的机制。
Necroptosis is an alternative programmed cell death pathway that is unleashed in the absence of apoptosis and mediated by signaling complexes containing receptor-interating protein kinase 1 (RIPK1) and RIPK3. This form of cell death has recently been implicated in host defense system to eliminate pathogen-infected cells. However, only a few viral species such as herpes simplex virus (HSV) and cytomegalovirus (CMV) have evolved mechanisms inhibiting necroptosis to overcome host antiviral defense, which is important for successful pathogenesis. Here, we show that the γ-herpesvirus Epstein–Barr virus (EBV) blocks necroptosis in EBV-infected human nasopharyngeal epithelial cells and nasopharyngeal carcinoma cells. Our findings indicate that EBV-encoded latent membrane protein 1 (LMP1), which lacks an RIP homotypic interaction motif (RHIM) domain, has mechanisms distinct from RHIM signaling competition to inhibit this necroptotic pathway. Intriguingly, LMP1 interacts directly with both RIPK1 and RIPK3 through its C-terminal activation region. More importantly, LMP1 can modulate the post-translational modification of the two receptor-interacting proteins. We then show that LMP1-mediated promotion of K63-polyubiquitinated RIPK1, suppression of RIPK1 protein expression and inhibition of K63-polyubiquitinated RIPK3 induced a switch in cell fate from necroptotic death to survival. These findings provide direct evidence for the suppression of necroptosis by EBV and define a mechanism of LMP1 to interrupt the initiation process of necroptosis before necrosome formation.
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影响因子：
16
作者：
Mandal P;Berger SB;Pillay S;Moriwaki K;Huang C;Guo H;Lich JD;Finger J;Kasparcova V;Votta B;Ouellette M;King BW;Wisnoski D;Lakdawala AS;DeMartino MP;Casillas LN;Haile PA;Sehon CA;Marquis RW;Upton J;Daley-Bauer LP;Roback L;Ramia N;Dovey CM;Carette JE;Chan FK;Bertin J;Gough PJ;Mocarski ES;Kaiser WJ
通讯作者：
Kaiser WJ
影响因子：
4.8
作者：
Kaiser, William J.;Sridharan, Haripriya;Mocarski, Edward S.
通讯作者：
Mocarski, Edward S.
影响因子：
64.8
作者：
DAWSON, CW;RICKINSON, AB;YOUNG, LS
通讯作者：
YOUNG, LS
影响因子：
16
作者：
Ea, CK;Deng, L;Chen, ZJJ
通讯作者：
Chen, ZJJ
翻译后修饰作为 TNF 诱导的坏死性凋亡的关键调节因子。
影响因子：
9
作者：
Liu X;Shi F;Li Y;Yu X;Peng S;Li W;Luo X;Cao Y
通讯作者：
Cao Y