Immunology Institute, Mount Sinai School of Medicine, New York, NY 10029, USA.
Immunol Res. 2012 Dec;54(1-3):214-26. doi: 10.1007/s12026-012-8321-7.
The mechanisms regulating cell survival and thus its corollary, cell death, have been intensively studied over the last two decades. Recent studies have shed new light into how non-degradative ubiquitination of the kinase RIPK1 is critical in determining this cell fate. In this review, we summarize recent findings on how ubiquitination of RIPK1 constitutes a survival signal through both NFκB-independent and NFκB-dependent mechanisms. However, in the absence of ubiquitination, RIPK1 becomes a death-signaling molecule capable of engaging both the caspase-dependent apoptosis machinery and the recently described RIPK3-dependent necroptosis machinery. Another layer of complexity is now emerging in that components of the ubiquitin-modifying machinery are themselves regulated by proteolytic processing. This survival/death regulatory mechanism has been best analyzed in the context of TNF receptor signaling, but it is likely that principles learned from TNFR may be applicable to other immune receptors including the antigen and Toll-like receptors.
在过去的二十年中，人们对调节细胞存活的机制进行了深入研究，细胞死亡是其必然结果。最近的研究揭示了激酶 RIPK1 的非降解泛素化如何在决定细胞命运方面起着关键作用。在这篇综述中，我们总结了最近的发现，即 RIPK1 的泛素化如何通过非 NFκB 依赖和 NFκB 依赖机制构成生存信号。然而，在缺乏泛素化的情况下，RIPK1 成为一种死亡信号分子，能够激活依赖半胱天冬酶的细胞凋亡机制和最近描述的依赖 RIPK3 的细胞坏死机制。现在出现了另一个复杂层面，即泛素修饰机制的组件本身受到蛋白水解处理的调节。这种生存/死亡调节机制在 TNF 受体信号转导的背景下得到了很好的分析，但从 TNFR 中获得的原则可能适用于其他免疫受体，包括抗原和 Toll 样受体。
