RIPK3 promotes cell death and NLRP3 inflammasome activation in the absence of MLKL.
RIPK3 promotes cell death and NLRP3 inflammasome activation in the absence of MLKL.
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DOI：
10.1038/ncomms7282
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发表时间：
2015-02-18
影响因子：
16.6
通讯作者：
Vince, James E.
中科院分区：
文献类型：
--
作者：
Lawlor, Kate E.;Khan, Nufail;Mildenhall, Alison;Gerlic, Motti;Croker, Ben A.;D'Cruz, Akshay A.;Hall, Cathrine;Spall, Sukhdeep Kaur;Anderton, Holly;Masters, Seth L.;Rashidi, Maryam;Wicks, Ian P.;Alexander, Warren S.;Mitsuuchi, Yasuhiro;Benetatos, Christopher A.;Condon, Stephen M.;Wong, W. Wei-Lynn;Silke, John;Vaux, David L.;Vince, James E.
RIPK 3及其底物MLKL是坏死性凋亡所必需的，坏死性凋亡是一种溶解性细胞死亡，通过释放细胞内分子引起炎症。RIPK 3是否以及如何以独立于MLKL和细胞裂解的方式驱动炎症仍不清楚。在这里，我们表明，LPS治疗后，或LPS诱导的坏死性凋亡，TLR衔接蛋白TRIF和抑制剂的凋亡蛋白（IAP：X-连锁IAP，细胞IAP 1和IAP 2）调节RIPK 3和MLKL泛素化。因此，当IAP不存在时，LPS触发RIPK 3激活半胱天冬酶-8，促进细胞凋亡和NLRP 3-半胱天冬酶-1激活，独立于RIPK 3激酶活性和MLKL。相反，在IAP和半胱天冬酶-8都不存在的情况下，RIPK 3激酶活性和MLKL对于TLR诱导的NLRP 3活化是必需的。与体外实验一致，白细胞介素-1（IL-1）依赖性自身抗体介导的关节炎在缺乏IAP的小鼠中加重，并且通过RIPK 3而不是MLKL的缺失而减轻。因此，RIPK 3可以促进NLRP 3炎性体和IL-1β炎性反应，而不依赖于MLKL和坏死性细胞死亡。 RIPK 3可以通过MLKL磷酸化引起坏死性细胞死亡，并激活NLRP 3炎性体。在这里，作者表明MLKL与RIPK 3激活NLRP 3有关，并强调了不同的IAP蛋白如何限制RIPK 3诱导的细胞凋亡、坏死性凋亡和IL-1分泌。
RIPK3 and its substrate MLKL are essential for necroptosis, a lytic cell death proposed to cause inflammation via the release of intracellular molecules. Whether and how RIPK3 might drive inflammation in a manner independent of MLKL and cell lysis remains unclear. Here we show that following LPS treatment, or LPS-induced necroptosis, the TLR adaptor protein TRIF and inhibitor of apoptosis proteins (IAPs: X-linked IAP, cellular IAP1 and IAP2) regulate RIPK3 and MLKL ubiquitylation. Hence, when IAPs are absent, LPS triggers RIPK3 to activate caspase-8, promoting apoptosis and NLRP3–caspase-1 activation, independent of RIPK3 kinase activity and MLKL. In contrast, in the absence of both IAPs and caspase-8, RIPK3 kinase activity and MLKL are essential for TLR-induced NLRP3 activation. Consistent with in vitro experiments, interleukin-1 (IL-1)-dependent autoantibody-mediated arthritis is exacerbated in mice lacking IAPs, and is reduced by deletion of RIPK3, but not MLKL. Therefore RIPK3 can promote NLRP3 inflammasome and IL-1β inflammatory responses independent of MLKL and necroptotic cell death. RIPK3 can cause necroptotic cell death via MLKL phosphorylation, and activate NLRP3 inflammasome. Here the authors show that MLKL is dispensable for NLRP3 activation by RIPK3, and highlight how different IAP proteins limit RIPK3 induced apoptosis, necroptosis and IL-1 secretion.
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