# Linear ubiquitination of p31comet by HOIP couples cytokine response with mitotic regulation

## TL;DR

This study shows how inflammation affects cell division by modifying a key protein, linking inflammation to cancer development.

## Contribution

The study reveals a new mechanism where HOIP linear ubiquitinates p31comet, connecting cytokine signaling to mitotic regulation.

## Key findings

- HOIP linear ubiquitinates p31comet at its C-terminal lysine residues after cytokine stimulation.
- Ubiquitinated p31comet has reduced binding to PLK1, enhancing its function in mitosis.
- HOIP deficiency causes prolonged mitotic duration and increased mitotic defects similar to p31comet knockout.

## Abstract

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.

Here, we report that the mitotic checkpoint protein p31comet (MAD2L1BP) is modified by linear ubiquitination via the E3 ubiquitin ligase HOIP after cytokine stimulation. HOIP-mediated polyubiquitination of p31comet occurs on its C-terminal lysine residues. Ubiquitinated p31comet displays reduced binding to PLK1, which phosphorylates and inactivates p31comet. Thus HOIP positively  regulates p31comet function. Consistent with this notion, HOIP-deficient cells exhibit prolonged mitotic duration similar to p31comet knockout. Mitotic defects are also more prevalent in cells without HOIP or p31comet. Moreover, compared with the cells expressing wild-type p31comet, cells expressing a ubiquitination-deficient p31comet mutant take more time to complete the M phase.

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 p31comet overexpressed cancer types.

The online version contains supplementary material available at 10.1186/s13578-025-01416-8.