PELI1 functions as a dual modulator of necroptosis and apoptosis by regulating ubiquitination of RIPK1 and mRNA levels of c-FLIP

Apoptosis and necroptosis are two distinct cell death mechanisms that may be activated in cells on stimulation by TNFα. It is still unclear, however, how apoptosis and necroptosis may be differentially regulated. Here we screened for E3 ubiquitin ligases that could mediate necroptosis. We found that...

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Published in:Proceedings of the National Academy of Sciences - PNAS 2017-11, Vol.114 (45), p.11944-11949
Main Authors: Wang, Huibing, Meng, Huyan, Li, Xingyan, Zhu, Kezhou, Dong, Kangyun, Mookhtiar, Adnan K., Wei, Huiting, Li, Ying, Sun, Shao-Cong, Yuan, Junying
Format: Article
Language:English
Subjects:
Activation
Apoptosis
Binding sites
Biological Sciences
c-FLIP protein
Caspase
Caspase-8
Cell death
Cells
Enzymes
FLIP protein
mRNA
Necroptosis
Ribonucleic acid
RNA
Rodents
Tumor necrosis factor-α
Ubiquitin
Ubiquitin-protein ligase
Ubiquitination
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Summary:Apoptosis and necroptosis are two distinct cell death mechanisms that may be activated in cells on stimulation by TNFα. It is still unclear, however, how apoptosis and necroptosis may be differentially regulated. Here we screened for E3 ubiquitin ligases that could mediate necroptosis. We found that deficiency of Pellino 1 (PELI1), an E3 ubiquitin ligase, blocked necroptosis. We show that PELI1 mediates K63 ubiquitination on K115 of RIPK1 in a kinase-dependent manner during necroptosis. Ubiquitination of RIPK1 by PELI1 promotes the formation of necrosome and execution of necroptosis. Although PELI1 is not directly involved in mediating the activation of RIPK1, it is indispensable for promoting the binding of activated RIPK1 with its downstream mediator RIPK3 to promote the activation of RIPK3 and MLKL. Inhibition of RIPK1 kinase activity blocks PELI1-mediated ubiquitination of RIPK1 in necroptosis. However, we show that PELI1 deficiency sensitizes cells to both RIPK1-dependent and RIPK1-independent apoptosis as a result of down-regulated expression of c-FLIP, an inhibitor of caspase-8. Finally, we show that Peli1 −/− mice are sensitized to TNFα-induced apoptosis. Thus, PELI1 is a key modulator of RIPK1 that differentially controls the activation of necroptosis and apoptosis.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.1715742114