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

Thumbnail Image

Embargo End Date

Authors

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

Document Type

Journal Article

Date

2019-02-07

Date Accepted

2018-11-07

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.

Citation

Molecular cell, 2019, 73 (3), pp. 413 - 428.e7

Source Title

Publisher

CELL PRESS

ISSN

1097-2765

eISSN

1097-4164

Research Team

Cell Death and Immunity

Notes