RIPK1 and Caspase-8 Ensure Chromosome Stability Independently of Their Role in Cell Death and Inflammation

Mol Cell. 2019 Feb 7;73(3):413-428.e7. doi: 10.1016/j.molcel.2018.11.010. Epub 2018 Dec 28.

Abstract

Receptor-interacting protein kinase (RIPK) 1 functions as a key mediator of tissue homeostasis via formation of Caspase-8 activating ripoptosome complexes, positively and negatively regulating apoptosis, necroptosis, and inflammation. Here, we report an unanticipated cell-death- and inflammation-independent function of RIPK1 and Caspase-8, promoting faithful chromosome alignment in mitosis and thereby ensuring genome stability. We find that ripoptosome complexes progressively form as cells enter mitosis, peaking at metaphase and disassembling as cells exit mitosis. Genetic deletion and mitosis-specific inhibition of Ripk1 or Caspase-8 results in chromosome alignment defects independently of MLKL. We found that Polo-like kinase 1 (PLK1) is recruited into mitotic ripoptosomes, where PLK1's activity is controlled via RIPK1-dependent recruitment and Caspase-8-mediated cleavage. A fine balance of ripoptosome assembly is required as deregulated ripoptosome activity modulates PLK1-dependent phosphorylation of downstream effectors, such as BUBR1. Our data suggest that ripoptosome-mediated regulation of PLK1 contributes to faithful chromosome segregation during mitosis.

Keywords: BUBR1; PLK1; RIPK1; cancer; caspase-8; cell cycle; cell death; chromosomal instability; mitosis; ripoptosome.

Publication types

  • Research Support, Non-U.S. Gov't
  • Video-Audio Media

MeSH terms

  • Aneuploidy
  • Animals
  • Apoptosis
  • CASP8 and FADD-Like Apoptosis Regulating Protein / genetics
  • CASP8 and FADD-Like Apoptosis Regulating Protein / metabolism
  • Caspase 8 / genetics
  • Caspase 8 / metabolism*
  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / metabolism
  • Chromosomal Instability*
  • Chromosome Segregation
  • Colonic Neoplasms / enzymology*
  • Colonic Neoplasms / genetics
  • Colonic Neoplasms / pathology
  • Fas-Associated Death Domain Protein / genetics
  • Fas-Associated Death Domain Protein / metabolism
  • Fibroblasts / enzymology*
  • Fibroblasts / pathology
  • HT29 Cells
  • Humans
  • Inflammation / enzymology
  • Inflammation / genetics
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mitosis*
  • Phosphorylation
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism
  • Receptor-Interacting Protein Serine-Threonine Kinases / deficiency
  • Receptor-Interacting Protein Serine-Threonine Kinases / genetics
  • Receptor-Interacting Protein Serine-Threonine Kinases / metabolism*
  • Signal Transduction

Substances

  • Bub1b protein, mouse
  • CASP8 and FADD-Like Apoptosis Regulating Protein
  • CFLAR protein, human
  • Cell Cycle Proteins
  • Cflar protein, mouse
  • FADD protein, human
  • Fadd protein, mouse
  • Fas-Associated Death Domain Protein
  • Proto-Oncogene Proteins
  • BUB1 protein, human
  • Protein-Serine-Threonine Kinases
  • RIPK1 protein, human
  • Receptor-Interacting Protein Serine-Threonine Kinases
  • Ripk1 protein, mouse
  • polo-like kinase 1
  • CASP8 protein, human
  • Casp8 protein, mouse
  • Caspase 8