MIND bomb 2 prevents RIPK1 kinase activity-dependent and -independent apoptosis through ubiquitylation of cFLIPL.

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 (cFLIPL), a catalytically inactive ...
homologue of caspase 8. Deletion of MIB2 did not impair the TNF-induced complex I formation that mediates NF-?B activation but significantly enhanced formation of cytosolic death-inducing signalling complex II. TNF-induced RIPK1 Ser166 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 cFLIPL 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 cFLIPL, respectively.
Mesh Terms:
Apoptosis, CASP8 and FADD-Like Apoptosis Regulating Protein, Cell Death, HCT116 Cells, HEK293 Cells, HeLa Cells, Humans, NF-kappa B, Receptor-Interacting Protein Serine-Threonine Kinases, Signal Transduction, Tumor Necrosis Factor-alpha, Ubiquitin-Protein Ligases, Ubiquitination
Commun Biol
Date: Dec. 19, 2020
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