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

ABSTRACT: Stimulation of TNFR1 by TNF? 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 TNF?-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 TNF? leads to RIPK1-independent apoptosis when NF-?B 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.TNF? can promote three distinct mechanisms of cell death: necroptosis, RIPK1-independent and dependent apoptosis. Here the authors show that TNF?-induced phosphorylation of RIPK1 in the intermediate domain by TAK1 plays a key role in regulating this decision.

SUBMITTER: Geng J 

PROVIDER: S-EPMC5572456 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature