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

Area of Science:

• Cell Biology
• Molecular Biology
• Genetics

Background:

• Receptor-interacting protein kinase 1 (RIPK1) is known to mediate tissue homeostasis through ripoptosome complexes, regulating apoptosis, necroptosis, and inflammation.
• The precise roles of RIPK1 and Caspase-8 in cellular processes beyond cell death are not fully understood.

Purpose of the Study:

• To investigate a previously unrecognized function of RIPK1 and Caspase-8 in mitosis.
• To elucidate the mechanism by which RIPK1 and Caspase-8 contribute to genome stability during cell division.

Main Methods:

• Utilized genetic deletion and mitosis-specific inhibition of Ripk1 and Caspase-8.
• Investigated the formation and disassembly of ripoptosome complexes during the cell cycle.
• Examined the interaction and regulation of Polo-like kinase 1 (PLK1) within mitotic ripoptosomes.

Main Results:

• RIPK1 and Caspase-8 promote faithful chromosome alignment in mitosis, independent of MLKL.
• Ripoptosome complexes form during mitosis, peaking at metaphase and disassembling during mitotic exit.
• PLK1 is recruited to mitotic ripoptosomes, with its activity regulated by RIPK1-dependent recruitment and Caspase-8-mediated cleavage.
• Dysregulated ripoptosome activity impacts PLK1-dependent phosphorylation of downstream targets like BUBR1, affecting chromosome segregation.

Conclusions:

• RIPK1 and Caspase-8 possess a critical, cell-death-independent function in ensuring genome stability by regulating chromosome alignment during mitosis.
• Ripoptosome-mediated regulation of PLK1 activity is essential for faithful chromosome segregation.