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Nat Commun. 2017 Aug 25;8(1):359. doi: 10.1038/s41467-017-00406-w.

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

Author information

1
Department of Cell Biology, Harvard Medical School, 240 Longwood Ave, Boston, MA, 02115, USA.
2
Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 26 Qiuyue Rd, PuDong District, Shanghai, 201210, China.
3
Horae Gene Therapy Center and Vector Core, and Department of Physiological Systems, University of Massachusetts Medical School, 368 Plantation Street, AS6-2049, Worcester, MA, 01605, USA.
4
Laboratory of Host Defense, WPI Immunology Frontier Research Center (IFReC), Osaka University, 3-1 Yamadaoka, Suita, Osaka, 565-0871, Japan.
5
Department of Cell Biology, Harvard Medical School, 240 Longwood Ave, Boston, MA, 02115, USA. jyuan@hms.harvard.edu.
6
Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 26 Qiuyue Rd, PuDong District, Shanghai, 201210, China. jyuan@hms.harvard.edu.

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.

PMID:
28842570
PMCID:
PMC5572456
DOI:
10.1038/s41467-017-00406-w
[Indexed for MEDLINE]
Free PMC Article

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