Linear ubiquitination of p31(comet) by HOIP couples cytokine response with mitotic regulation.

BACKGROUND: Inflammation and genomic instability are among the hallmarks of human cancer. Proinflammatory cytokines induce DNA damage through the accumulation of reactive oxygen and nitrogen species (RONS), which often leads to base alternations. The link between proinflammatory cytokines and chromosomal instability remains largely elusive. RESULTS: Here, we report that the mitotic checkpoint protein p31(comet) (MAD2L1BP) is modified by linear ubiquitination via the E3 ubiquitin ligase HOIP after cytokine stimulation. HOIP-mediated polyubiquitination of p31(comet) occurs on its C-terminal lysine residues. Ubiquitinated p31(comet) displays reduced binding to PLK1, which phosphorylates and inactivates p31(comet). Thus HOIP positively  regulates p31(comet) function. Consistent with this notion, HOIP-deficient cells exhibit prolonged mitotic duration similar to p31(comet) knockout. Mitotic defects are also more prevalent in cells without HOIP or p31(comet). Moreover, compared with the cells expressing wild-type p31(comet), cells expressing a ubiquitination-deficient p31(comet) mutant take more time to complete the M phase. CONCLUSIONS: Our results together uncover a mechanistic link between the proinflammatory cytokines and the mitotic checkpoint pathways. This molecular switch could be explored as a potential therapeutic target in inflammation-driving or p31(comet) overexpressed cancer types.