RIPK1 and Caspase-8 Ensure Chromosome Stability Independently of Their Role in Cell Death and Inflammation.
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Date
2019-02-07Author
Liccardi, G
Ramos Garcia, L
Tenev, T
Annibaldi, A
Legrand, AJ
Robertson, D
Feltham, R
Anderton, H
Darding, M
Peltzer, N
Dannappel, M
Schünke, H
Fava, LL
Haschka, MD
Glatter, T
Nesvizhskii, A
Schmidt, A
Harris, PA
Bertin, J
Gough, PJ
Villunger, A
Silke, J
Pasparakis, M
Bianchi, K
Meier, P
Type
Journal Article
Metadata
Show full item recordAbstract
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.
Collections
Subject
HT29 Cells
Fibroblasts
Animals
Mice, Inbred C57BL
Mice, Knockout
Humans
Mice
Colonic Neoplasms
Aneuploidy
Chromosomal Instability
Inflammation
Protein-Serine-Threonine Kinases
Cell Cycle Proteins
Proto-Oncogene Proteins
Signal Transduction
Chromosome Segregation
Mitosis
Apoptosis
Phosphorylation
Caspase 8
CASP8 and FADD-Like Apoptosis Regulating Protein
Fas-Associated Death Domain Protein
Receptor-Interacting Protein Serine-Threonine Kinases
Research team
Cell Death and Immunity
Language
eng
Date accepted
2018-11-07
License start date
2019-02
Citation
Molecular cell, 2019, 73 (3), pp. 413 - 428.e7
Publisher
CELL PRESS
Except where otherwise noted, this item's license is described
as
https://creativecommons.org/licenses/by/4.0
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