Gao Yifeng, Yin Qing, Gamallat Yaser, Grant Michael G, Snell Aidan H, Shi Xingxing, Ulstad Lara N, Singh Arshita, Chen Tingan, Johnson Joseph O, Avram Dorina, Wan Lixin
Department of Molecular Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, 33612, USA.
Department of Molecular Biosciences, College of Arts and Sciences, University of South Florida, Tampa, FL, 33620, USA.
Cell Biosci. 2025 Jun 3;15(1):75. doi: 10.1186/s13578-025-01416-8.
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 p31 (MAD2L1BP) is modified by linear ubiquitination via the E3 ubiquitin ligase HOIP after cytokine stimulation. HOIP-mediated polyubiquitination of p31 occurs on its C-terminal lysine residues. Ubiquitinated p31 displays reduced binding to PLK1, which phosphorylates and inactivates p31. Thus HOIP positively regulates p31 function. Consistent with this notion, HOIP-deficient cells exhibit prolonged mitotic duration similar to p31 knockout. Mitotic defects are also more prevalent in cells without HOIP or p31. Moreover, compared with the cells expressing wild-type p31, cells expressing a ubiquitination-deficient p31 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 p31 overexpressed cancer types.
炎症和基因组不稳定是人类癌症的标志之一。促炎细胞因子通过活性氧和氮物种（RONS）的积累诱导DNA损伤，这通常会导致碱基改变。促炎细胞因子与染色体不稳定之间的联系在很大程度上仍然难以捉摸。
在此，我们报告有丝分裂检查点蛋白p31（MAD2L1BP）在细胞因子刺激后通过E3泛素连接酶HOIP被线性泛素化修饰。HOIP介导的p31多聚泛素化发生在其C末端赖氨酸残基上。泛素化的p31与PLK1的结合减少，PLK1使p31磷酸化并使其失活。因此，HOIP正向调节p31的功能。与此观点一致，HOIP缺陷细胞表现出与p31基因敲除相似的延长的有丝分裂持续时间。在没有HOIP或p31的细胞中，有丝分裂缺陷也更普遍。此外，与表达野生型p31的细胞相比，表达泛素化缺陷型p31突变体的细胞完成M期需要更多时间。
我们的结果共同揭示了促炎细胞因子与有丝分裂检查点途径之间的机制联系。这种分子开关可作为炎症驱动或p31过表达癌症类型的潜在治疗靶点进行探索。
