Horae Gene Therapy Center and Vector Core; Department of Microbiology and Physiological Systems
Cell Biology | Cellular and Molecular Physiology
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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DOI of Published Version
Nat Commun. 2017 Aug 25;8(1):359. doi: 10.1038/s41467-017-00406-w. Link to article on publisher's site
Geng J, Ito Y, Shi L, Amin P, Chu J, Ouchida AT, Mookhtiar AK, Zhao H, Xu D, Shan B, Najafov A, Gao G, Akira S, Yuan J. (2017). Regulation of RIPK1 activation by TAK1-mediated phosphorylation dictates apoptosis and necroptosis. Open Access Articles. https://doi.org/10.1038/s41467-017-00406-w. Retrieved from https://escholarship.umassmed.edu/oapubs/3235
Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 License.