Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 114, Issue 45, Pages 11944-11949Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1715742114
Keywords
necroptosis; apoptosis; Peli1; ubiquitination; TNF
Categories
Funding
- National Institute on Aging [1R01AG047231]
- National Institute of Neurological Disorders and Stroke [1R01NS082257]
- Chinese Academy of Sciences
- National Key R&D Program of China
- China Ministry of Science and Technology Program [2014ZX09102001-002]
- China National Natural Science Foundation [31530041]
- National Science Foundation in China
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Apoptosis and necroptosis are two distinct cell death mechanisms that may be activated in cells on stimulation by TNF alpha. 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 TNF alpha-induced apoptosis. Thus, PELI1 is a key modulator of RIPK1 that differentially controls the activation of necroptosis and apoptosis.
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