MIND bomb 2 prevents RIPK1 kinase activity-dependent and -independent apoptosis through ubiquitylation of cFLIP L

Commun Biol. 2021 Jan 19;4(1):80. doi: 10.1038/s42003-020-01603-y.

Abstract

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-κB 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / drug effects
  • CASP8 and FADD-Like Apoptosis Regulating Protein / metabolism*
  • Cell Death / drug effects
  • HCT116 Cells
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • NF-kappa B / metabolism
  • Receptor-Interacting Protein Serine-Threonine Kinases / metabolism
  • Signal Transduction / drug effects
  • Tumor Necrosis Factor-alpha / metabolism
  • Ubiquitin-Protein Ligases / metabolism*
  • Ubiquitin-Protein Ligases / physiology
  • Ubiquitination / drug effects

Substances

  • CASP8 and FADD-Like Apoptosis Regulating Protein
  • NF-kappa B
  • Tumor Necrosis Factor-alpha
  • MIB2 protein, human
  • Ubiquitin-Protein Ligases
  • RIPK1 protein, human
  • Receptor-Interacting Protein Serine-Threonine Kinases