期刊
COMMUNICATIONS BIOLOGY
卷 4, 期 1, 页码 -出版社
NATURE RESEARCH
DOI: 10.1038/s42003-020-01603-y
关键词
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资金
- Japan Society for the Promotion of Science (JSPS) [17H04069, 20H03475, 20K09231, 17K19533, 26110003]
- Japan Agency for Medical Research and Development through AMED-CREST [20gm1210002]
- Private University Research Branding project from the Ministry of Education, Culture, Sports, Science, and Technology, Japan
- Toho University Grant for Research Initiative Program (TUGRIP) from Toho University, Japan
- Grants-in-Aid for Scientific Research [20H03475, 17K19533, 20K09231] Funding Source: KAKEN
The E3 ligase MIB2 ubiquitylates apoptosis-inhibitor cFLIP, suppressing RIPK1 kinase activity-dependent and -independent apoptosis. Deletion of MIB2 enhances RIPK1 kinase activity and impairs ubiquitylation of cFLIP(L), resulting in increased apoptosis.
Mind bomb 2 (MIB2) is an E3 ligase involved in Notch signalling and attenuates TNF-induced apoptosis through ubiquitylation of receptor-interacting protein kinase 1 (RIPK1) and cylindromatosis. Here we show that MIB2 bound and conjugated K48- and K63-linked polyubiquitin chains to a long-form of cellular FLICE-inhibitory protein (cFLIP(L)), a catalytically inactive homologue of caspase 8. Deletion of MIB2 did not impair the TNF-induced complex I formation that mediates NF-kappa B activation but significantly enhanced formation of cytosolic death-inducing signalling complex II. TNF-induced RIPK1 Ser(166) phosphorylation, a hallmark of RIPK1 death-inducing activity, was enhanced in MIB2 knockout cells, as was RIPK1 kinase activity-dependent and -independent apoptosis. Moreover, RIPK1 kinase activity-independent apoptosis was induced in cells expressing cFLIP(L) mutants lacking MIB2-dependent ubiquitylation. Together, these results suggest that MIB2 suppresses both RIPK1 kinase activity-dependent and -independent apoptosis, through suppression of RIPK1 kinase activity and ubiquitylation of cFLIP(L), respectively. Nakabayashi et al find that the E3 ligase MIB2 ubiquitylates the apoptosis-inhibitor cFLIP and that deletion of MIB2 enhances both RIPK1 kinase-dependent and -independent apoptosis through an increase in RIPK1 kinase activity and impairment of ubiquitylation of cFLIP(L), respectively.
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