Title
Regulation of RIPK1 activation by TAK1-mediated phosphorylation dictates apoptosis and necroptosis
UMMS Affiliation
Horae Gene Therapy Center and Vector Core; Department of Microbiology and Physiological Systems
Publication Date
2017-08-25
Document Type
Article
Disciplines
Cell Biology | Cellular and Molecular Physiology
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.
Keywords
Apoptosis, Necroptosis
Rights and Permissions
Copyright © The Author(s) 2017. Open Access. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
DOI of Published Version
10.1038/s41467-017-00406-w
Source
Nat Commun. 2017 Aug 25;8(1):359. doi: 10.1038/s41467-017-00406-w. Link to article on publisher's site
Journal/Book/Conference Title
Nature communications
Related Resources
PubMed ID
28842570
Repository Citation
Geng, Jiefei; Ito, Yasushi; Shi, Linyu; Amin, Palak; Chu, Jiachen; Ouchida, Amanda Tomie; Mookhtiar, Adnan Kasim; Zhao, Heng; Xu, Daichao; Shan, Bing; Najafov, Ayaz; Gao, Guangping; Akira, Shizuo; and Yuan, Junying, "Regulation of RIPK1 activation by TAK1-mediated phosphorylation dictates apoptosis and necroptosis" (2017). Open Access Articles. 3235.
https://escholarship.umassmed.edu/oapubs/3235
Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 License.