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

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

Author information

1
The Breast Cancer Now Toby Robins Research Centre, Institute of Cancer Research, Mary-Jean Mitchell Green Building, Chester Beatty Laboratories, 237 Fulham Road, London SW3 6JB, UK.
2
The Walter and Eliza Hall Institute, 1G Royal Parade, Parkville, Victoria 3052, Australia.
3
The Breast Cancer Now Toby Robins Research Centre, Institute of Cancer Research, Mary-Jean Mitchell Green Building, Chester Beatty Laboratories, 237 Fulham Road, London SW3 6JB, UK; Centre for Cell Death, Cancer, and Inflammation (CCCI), UCL Cancer Institute, University College, London WC1E 6BT, UK.
4
Centre for Cell Death, Cancer, and Inflammation (CCCI), UCL Cancer Institute, University College, London WC1E 6BT, UK.
5
Institute for Genetics, Centre for Molecular Medicine (CMMC) and Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, 50931 Cologne, Germany.
6
Division of Dev. Immunology, Biocenter, Medical University of Innsbruck, Innsbruck, A-6020, Austria.
7
Proteomics Core Facility, Biocentrum of the University of Basel, Basel, Switzerland; Max Planck Institute for Terrestrial Microbiology, Karl-von-Frisch Str. 10, 35043 Marburg, Germany.
8
Department of Pathology, Department of Computational Medicine & Bioinformatics, University of Michigan, Ann Arbor, MI, USA.
9
Proteomics Core Facility, Biocentrum of the University of Basel, Basel, Switzerland.
10
Pattern Recognition Receptor Discovery Performance Unit, Immuno-Inflammation Therapeutic Area, GlaxoSmithKline, Collegeville, PA 19426, USA.
11
Division of Dev. Immunology, Biocenter, Medical University of Innsbruck, Innsbruck, A-6020, Austria; Tyrolean Cancer Research Institute, A-6020 Innsbruck, Austria.
12
The Breast Cancer Now Toby Robins Research Centre, Institute of Cancer Research, Mary-Jean Mitchell Green Building, Chester Beatty Laboratories, 237 Fulham Road, London SW3 6JB, UK; Barts Cancer Institute, Queen Mary, John Vane Science Centre, University of London, Charterhouse Square, London EC1M 6BQ, UK.
13
The Breast Cancer Now Toby Robins Research Centre, Institute of Cancer Research, Mary-Jean Mitchell Green Building, Chester Beatty Laboratories, 237 Fulham Road, London SW3 6JB, UK. Electronic address: pmeier@icr.ac.uk.

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

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