The NAD-dependent deacetylase SIRT2 is required for programmed necrosis

摘要

死亡配体TNF-α通过刺激一个包含“受体相互作用蛋白-1"(RIP1)和“受体相互作用蛋白-3”(RIP3)的复合物的形成来激发坏死。TorernrnFinkel及其同事通过对小鼠进行研究发现，“依赖于NAD的脱乙酰基酶”SIRT2作为组成成分结合到RIP3上。如果没有SIRT2，RIP1-RIP3rn复合物不会在TNF-α刺激后形成，坏死就不会发生。RIP1是依赖于SIRT2的脱乙酰化作用的目标，其乙酰化作用调控RIP1-RIP3复合物的形成和TNF-α刺激的坏死。在“缺血再灌注”受伤过程中(在该过程中坏死普遍发生)，RIP1被以依赖于SIRT2的方式脱乙酰。本文作者进而发现，缺失Sirt2基因的心脏或用SIRT2的药物抑制因子处理过的心脏基本rn上会受到保护而不发生缺血性受伤。因此，SIRT2是程序化坏死的一个重要调控因子，是防止坏死性受伤中一个有希望的药物作用目标。%Although initially viewed as unregulated, increasing evidence suggests that cellular necrosis often proceeds through a specific molecular program. In particular, death ligands such as tumour necrosis factor (TNF)-a activate necrosis by stimulating the formation of a complex containing receptor-interacting protein 1 (RIP1) and receptor-interacting protein 3 (RIP3). Relatively little is known regarding how this complex formation is regulated. Here, we show that the NAD-dependent deacetylase SIRT2 binds constitutively to RIP3 and that deletion or knockdown of SIRT2 prevents formation of the RIP1-RIP3 complex in mice. Furthermore, genetic or pharmacological inhibition of SIRT2 blocks cellular necrosis induced by TNF-α. We further demonstrate that RIP1 is a critical target of SIRT2-dependent deacetylation. Using gain- and loss-of-function mutants, we demonstrate that acetylation of RIP1 lysine 530 modulates RIP1-RIP3 complex formation and TNF-α-stimulated necrosis. In the setting of ischaemia-reperfusion injury, RIP1 is deacetylated in a SIRT2-dependent fashion. Furthermore, the hearts of Sirt2~(-/-) mice, or wild-type mice treated with a specific pharmacological inhibitor of SIRT2, show marked protection from ischaemic injury. Taken together, these results implicate SIRT2 as an important regulator of programmed necrosis and indicate that inhibitors of this deacetylase may constitute a novel approach to protect against necrotic injuries, including ischaemic stroke and myocardial infarction.