A role for tumor necrosis factor receptor-2 and receptor-interacting protein in programmed necrosis and antiviral responses
A role for tumor necrosis factor receptor-2 and receptor-interacting protein in programmed necrosis and antiviral responses
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DOI：
10.1074/jbc.m305633200
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发表时间：
2003-12-19
影响因子：
4.8
通讯作者：
Lenardo, MJ
中科院分区：
文献类型：
--
作者：
Chan, FKM;Shisler, J;Lenardo, MJ
肿瘤坏死因子 (TNF) 受体 (TNFR) 超家族的成员是细胞凋亡的有效调节剂，细胞凋亡过程对于维持免疫稳态非常重要。最近的证据表明，TNFR-1、Fas 和 TRAIL 受体也可以触发另一种形式的细胞死亡，这种死亡在形态上不同于细胞凋亡。由于需要包括丝氨酸/苏氨酸蛋白激酶受体相互作用蛋白（RIP）在内的不同分子成分，我们将这种细胞死亡的替代形式称为“程序性坏死”。我们证明 TNFR-2 信号传导可以通过 TNFR-1 增强程序性坏死。当细胞在随后激活 TNFR-1 之前通过 TNFR-2 进行预刺激时，观察到细胞死亡增强以及 RIP 向 TNFR-1 复合物的募集。然而，TNF 诱导的程序性坏死通常受到 RIP 的 caspase-8 切割的抑制。为了确定 RIP 和程序性坏死的生理意义，我们用痘苗病毒 (VV) 感染 Jurkat 细胞，发现 VV 感染的细胞响应 TNF 而发生程序性坏死，但 RIP 的缺陷使受感染的细胞免于 TNF 诱导的细胞毒性。此外，TNFR-2(-/-)小鼠在VV感染期间表现出肝脏炎症减轻和病毒清除缺陷。有趣的是，含有死亡效应结构域的蛋白质（例如 MC159、E8、K13 和细胞 FLIP）可有效抑制程序性坏死，但凋亡抑制剂 Bcl-x(L)、p35 和 XIAP 则不然。因此，TNFR-2信号传导和半胱天冬酶抑制促进了TNF诱导的程序性坏死，并且可能在控制病毒感染中发挥作用。
Members of the tumor necrosis factor (TNF) receptor (TNFR) superfamily are potent regulators of apoptosis, a process that is important for the maintenance of immune homeostasis. Recent evidence suggests that TNFR-1 and Fas and TRAIL receptors can also trigger an alternative form of cell death that is morphologically distinct from apoptosis. Because distinct molecular components including the serine/threonine protein kinase receptor-interacting protein ( RIP) are required, we have referred to this alternative form of cell death as "programmed necrosis." We show that TNFR-2 signaling can potentiate programmed necrosis via TNFR-1. When cells were pre-stimulated through TNFR-2 prior to subsequent activation of TNFR-1, enhanced cell death and recruitment of RIP to the TNFR-1 complex were observed. However, TNF-induced programmed necrosis was normally inhibited by caspase-8 cleavage of RIP. To ascertain the physiological significance of RIP and programmed necrosis, we infected Jurkat cells with vaccinia virus (VV) and found that VV-infected cells underwent programmed necrosis in response to TNF, but deficiency of RIP rescued the infected cells from TNF-induced cytotoxicity. Moreover, TNFR-2(-/-) mice exhibited reduced inflammation in the liver and defective viral clearance during VV infection. Interestingly, death effector domain-containing proteins such as MC159, E8, K13, and cellular FLIP, but not the apoptosis inhibitors Bcl-x(L), p35, and XIAP, potently suppressed programmed necrosis. Thus, TNF-induced programmed necrosis is facilitated by TNFR-2 signaling and caspase inhibition and may play a role in controlling viral infection.