Journal article

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

Gianmaria Liccardi, Laura Ramos Garcia, Tencho Tenev, Alessandro Annibaldi, Arnaud J Legrand, David Robertson, Rebecca Feltham, Holly Anderton, Maurice Darding, Nieves Peltzer, Marius Dannappel, Hannah Schunke, Luca L Fava, Manuel D Haschka, Timo Glatter, Alexey Nesvizhskii, Alexander Schmidt, Philip A Harris, John Bertin, Peter J Gough Show all

MOLECULAR CELL | CELL PRESS | Published : 2019

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 ..

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Grants

Awarded by Breast Cancer Now


Awarded by Medical Research Council (MRC)


Awarded by Komen Promise


Awarded by Austrian Science Fund (FWF)


Awarded by ERC grant


Awarded by NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES


Funding Acknowledgements

We would like to thank Erich Nigg, Tony Letai, Stephan Geley, Geert Kops, and Shaomeng Wang, Henning Walczak, and Andrew Oberst for reagents. We also thank members of the Meier laboratory for helpful discussions. We would like to thank the IHC facility of the Royal Marsden for support. We would like to thank Ben Atkinson, Hella Baumann, and Frederick Wallberg of the Intelligent imaging facility at the ICR for their support with the advanced spinning disc. We would like to apologize to the many authors whose work we could not cite due to space restrictions. Work in the Meier lab is funded by Breast Cancer Now (CTR-QR14-007), Medical Research Council (MRC) (MR/M019217/1), and Komen Promise (PG12220321). A.V. is supported by the Austrian Science Fund (FWF; I1298, P26856, W1101). M.D. and N.M.P. are supported by ERC. M.P. and M.D are funded by the ERC grant (grant agreement no. 323040). We acknowledge NHS funding to the NIHR Biomedical Research Centre.