Regulation of RIPK1 activation by TAK1-mediated phosphorylation dictates apoptosis and necroptosis.
Regulation of RIPK1 activation by TAK1-mediated phosphorylation dictates apoptosis and necroptosis.
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通过TAK1介导的磷酸化来调节RIPK1激活，决定了凋亡和坏死性。
DOI：
10.1038/s41467-017-00406-w
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发表时间：
2017-08-25
影响因子：
16.6
通讯作者：
Yuan J
中科院分区：
文献类型：
--
作者：
Geng J;Ito Y;Shi L;Amin P;Chu J;Ouchida AT;Mookhtiar AK;Zhao H;Xu D;Shan B;Najafov A;Gao G;Akira S;Yuan J
TNFα刺激TNFR 1可促进三种不同的细胞死亡机制：坏死性凋亡、RIPK 1非依赖性和依赖性凋亡。细胞如何决定以何种方式死亡尚不清楚。在这里，我们报道了TNFα诱导的TAK 1对RIPK 1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。以磷酸化丝氨酸321为标志物，我们发现当放线菌酮抑制NF-κB活化时，TNFα诱导的RIPK 1中间结构域的瞬时磷酸化导致RIPK 1非依赖性凋亡。另一方面，阻断Ser 321磷酸化促进RIPK 1活化及其与FADD的相互作用以介导RIPK 1依赖性凋亡（RDA）。最后，TAK 1在多个位点持续磷酸化RIPK 1中间结构域促进其与RIPK 3的相互作用和坏死性凋亡。因此，TAK 1介导的RIPK 1磷酸化的缺失、瞬时和持续水平可能代表TNF-RSC中的不同状态，从而决定三种替代细胞死亡机制的激活，即RDA、RIPK 1非依赖性细胞凋亡和坏死性凋亡。TNFα可促进三种不同的细胞死亡机制：坏死性凋亡、RIPK 1非依赖性和依赖性凋亡。在这里，作者表明，TNFα诱导的TAK 1在中间结构域的RIPK 1磷酸化在调节这一决定中起着关键作用。
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.
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影响因子：
64.5
作者：
Huttlin EL;Jedrychowski MP;Elias JE;Goswami T;Rad R;Beausoleil SA;Villén J;Haas W;Sowa ME;Gygi SP
通讯作者：
Gygi SP
影响因子：
4.8
作者：
Blonska, M;Shambharkar, PB;Lin, X
通讯作者：
Lin, X
影响因子：
16
作者：
Ea, CK;Deng, L;Chen, ZJJ
通讯作者：
Chen, ZJJ
影响因子：
10.5
作者：
Lin, Y;Devin, A;Liu, ZG
通讯作者：
Liu, ZG
影响因子：
30.5
作者：
Sato, S;Sanjo, H;Akira, S
通讯作者：
Akira, S