Kawasaki disease is a systemic vasculitis predominantly affecting children and is now recognized as being driven by B-cell-mediated immune dysregulation. Yet, the molecular events underlying aberrant B-cell activation have remained poorly understood.
The research team observed that USP22 is highly and specifically expressed in B cells from KD patients, where B-cell receptor (BCR) signaling is markedly enhanced. Treatment with a USP22 inhibitor partially reversed this hyperactivation. Conversely, B-cell-specific deletion of Usp22 in mice severely impaired BCR signaling—an opposite phenotype to that seen in KD. Metabolically, B cells from KD patients exhibited elevated oxidative phosphorylation and glycolysis, while USP22 deficiency reduced oxidative phosphorylation, and USP22 inhibitor treatment lowered the heightened oxidative phosphorylation in patient B cells.
Identifying the mechanism: USP22-CHD4-CD19 axis
Through yeast two-hybrid screening and co-immunoprecipitation, the team identified CHD4 as a novel substrate of USP22. USP22 stabilizes CHD4 via deubiquitination, and CHD4 subsequently acts on the promoter region of the Cd19 gene to regulate its expression. CD19, a pivotal signaling molecule on the B-cell surface, is regarded as a master controller of B-cell activation.
The CD19 downstream PI3K-AKT-mTOR axis was impaired in USP22-deficient B cells, resulting in defective oxidative phosphorylation. Beyond metabolism, the team found that USP22 promotes F-actin aggregation by regulating the WASP-DOCK8 axis downstream of CD19 signaling, facilitating cytoskeletal remodeling and antigen internalization following BCR stimulation.
Multiple roles of the USP22-CHD4 axis
In B-cell development, USP22 deficiency weakened BCR signaling, impaired maintenance of follicular B cells, and promoted expansion of marginal zone B cells. Functionally, Usp22 knockout mice exhibited suppressed T-cell-dependent immune responses, compromised antiviral defense against LCMV-Armstrong virus, and disrupted germinal center formation.
In summary, this study has for the first time revealed the molecular mechanism by which USP22, as an innate immune regulatory factor, affects the humoral immune response through regulating B cell differentiation, activation, and BCR signal transduction. The findings not only elucidate the pathological mechanism of B-cell hyperactivation in Kawasaki disease but also lay a molecular foundation for developing targeted therapeutic strategies.
Science Bulletin
Experimental study