Regulation of RIPK1 activation by TAK1-mediated phosphorylation dictates apoptosis and necroptosis
Geng, Jiefei ; Ito, Yasushi ; Shi, Linyu ; Amin, Palak ; Chu, Jiachen ; Ouchida, Amanda Tomie ; Mookhtiar, Adnan Kasim ; Zhao, Heng ; Xu, Daichao ; Shan, Bing ... show 4 more
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Abstract
Stimulation of TNFR1 by TNFalpha 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 TNFalpha-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 TNFalpha leads to RIPK1-independent apoptosis when NF-kappaB 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.TNFalpha can promote three distinct mechanisms of cell death: necroptosis, RIPK1-independent and dependent apoptosis. Here the authors show that TNFalpha-induced phosphorylation of RIPK1 in the intermediate domain by TAK1 plays a key role in regulating this decision.
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Nat Commun. 2017 Aug 25;8(1):359. doi: 10.1038/s41467-017-00406-w. Link to article on publisher's site