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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.
