@article{d5ca3e95b3e341aa9ffd8c4b8f6a9a66,
title = "RIPK1 and Caspase-8 Ensure Chromosome Stability Independently of Their Role in Cell Death and Inflammation",
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{\textquoteright}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, cancer, caspase-8, cell cycle, cell death, chromosomal instability, mitosis, PLK1, RIPK1, ripoptosome",
author = "Gianmaria Liccardi and {Ramos Garcia}, Laura and Tencho Tenev and Alessandro Annibaldi and Legrand, {Arnaud J.} and David Robertson and Rebecca Feltham and Holly Anderton and Maurice Darding and Nieves Peltzer and Marius Dannappel and Hannah Sch{\"u}nke and Fava, {Luca L.} and Haschka, {Manuel D.} and Timo Glatter and Alexey Nesvizhskii and Alexander Schmidt and Harris, {Philip A.} and John Bertin and Gough, {Peter J.} and Andreas Villunger and John Silke and Manolis Pasparakis and Katiuscia Bianchi and Pascal Meier",
note = "Funding Information: 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. Funding Information: 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. Publisher Copyright: {\textcopyright} 2018 The Authors",
year = "2019",
month = feb,
day = "7",
doi = "10.1016/j.molcel.2018.11.010",
language = "English",
volume = "73",
pages = "413--428.e7",
journal = "Molecular Cell",
issn = "1097-2765",
publisher = "Elsevier",
number = "3",
}
