Cbx4 governs HIF-1 to involve in Th9 cell differentiation promoting asthma by its SUMO E3 ligase activity

The potential role of polycomb chromobox 4 (Cbx4), as a small ubiquitin-like ligase (SUMO) E3 ligase, in the development and exacerbation of asthma remains unclear. Hypoxia inducible factor-1 (HIF-1) is a key transcription factor in the cellular response to hypoxia and contributes to the pathogenesis and progression of a range of diseases, including asthma. Here, we aimed to investigate the interaction of Cbx4 with Hypoxia inducible factor-1 alpha (HIF-1 alpha) and the potent mechanism of action in asthma progression. In present study, in vitro and ex vivo results demonstrated that Cbx4 interacts with HIF-1 alpha protein through its SUMO E3 ligase activity and enhances the sumoylation, which increases HIF-1 transactivation through Cbx4 and promotes the differentiation of Th9 cells, then in turn promotes the process of asthma. Treatment of inhibitors targeting SUMO E3 ligase activity of Cbx4 or HIF-1 alpha can effectively reduce HIF-1 alpha activation and differentiation of Th9 cells, which further attenuates the asthma in mouse model. Current results collectively demonstrated Cbx4 can govern HIF-1 alpha to involve in Th9 cell differentiation promoting asthma by its SUMO E3 ligase activity, providing a new direction for clinical treatment of asthma.