TAK1介导的磷酸化对RIPK1活化的调控决定了细胞凋亡和坏死性坏死。,Nature Communications

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TAK1介导的磷酸化对RIPK1活化的调控决定了细胞凋亡和坏死性坏死。
Nature Communications ( IF 14.7 ) Pub Date : 2017-08-25 , DOI: 10.1038/s41467-017-00406-w
Jiefei Geng , Yasushi Ito , Linyu Shi , Palak Amin , Jiachen Chu , Amanda Tomie Ouchida , Adnan Kasim Mookhtiar , Heng Zhao , Daichao Xu , Bing Shan , Ayaz Najafov , Guangping Gao , Shizuo Akira , Junying Yuan

TNFα刺激TNFR1可以促进细胞死亡的三种不同的替代机制：坏死病，独立于RIPK1和依赖于细胞凋亡。细胞如何决定死亡的方式尚不清楚。在这里，我们报告说，TAK1介导的TNFα诱导的RIPK1在中间结构域的磷酸化在调节这一关键决定中起着关键作用。使用磷酸化Ser321作为标记，我们表明当环己酰亚胺抑制NF-κB活化时，TNFα诱导的RIPK1中间结构域的瞬时磷酸化导致RIPK1依赖性凋亡。另一方面，阻断Ser321磷酸化可促进RIPK1活化及其与FADD的相互作用，以介导RIPK1依赖性细胞凋亡（RDA）。最后，TAK1在多个位点对RIPK1中间结构域的持续磷酸化促进了其与RIPK3的相互作用和坏死性坏死。因此，TAK1介导的RIPK1磷酸化的缺乏，瞬时和持续水平可能代表TNF-RSC中的不同状态，以指示三种另类细胞死亡机制的激活：RDA，独立于RIPK1的细胞凋亡和坏死性坏死.TNFα可以促进三种不同的细胞死亡机制：坏死性坏死，RIPK1依赖性和依赖性凋亡。在这里，作者表明，由TAK1介导的TNFα诱导的RIPK1在中间结构域的磷酸化在调节这一决定中起着关键作用。

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Regulation of RIPK1 activation by TAK1-mediated phosphorylation dictates apoptosis and necroptosis.

Stimulation of TNFR1 by TNFα can promote three distinct alternative mechanisms of cell death: necroptosis, RIPK1-independent and -dependent apoptosis. How cells decide which way to die is unclear. Here, we report that TNFα-induced phosphorylation of RIPK1 in the intermediate domain by TAK1 plays a key role in regulating this critical decision. Using phospho-Ser321 as a marker, we show that the transient phosphorylation of RIPK1 intermediate domain induced by TNFα leads to RIPK1-independent apoptosis when NF-κB activation is inhibited by cycloheximide. On the other hand, blocking Ser321 phosphorylation promotes RIPK1 activation and its interaction with FADD to mediate RIPK1-dependent apoptosis (RDA). Finally, sustained phosphorylation of RIPK1 intermediate domain at multiple sites by TAK1 promotes its interaction with RIPK3 and necroptosis. Thus, absent, transient and sustained levels of TAK1-mediated RIPK1 phosphorylation may represent distinct states in TNF-RSC to dictate the activation of three alternative cell death mechanisms, RDA, RIPK1-independent apoptosis and necroptosis.TNFα can promote three distinct mechanisms of cell death: necroptosis, RIPK1-independent and dependent apoptosis. Here the authors show that TNFα-induced phosphorylation of RIPK1 in the intermediate domain by TAK1 plays a key role in regulating this decision.

更新日期：2017-08-25

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