Regulation of RIPK1 Activation by TAK1-mediated Phosphorylation Dictates Apoptosis and Necroptosis

Overview

Journal Nat Commun

Specialty Biology

Date 2017 Aug 27

PMID 28842570

Citations 164

Authors

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

Affiliations

Soon will be listed here.

Abstract

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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