Ran You, Yuteng Jiang, Yingyi Xu, Qianying Liu, Menglei Gu, Yue Zhang, Zhanjun Jia, Mengqiu Wu, Mi Bai, Aihua Zhang
Podocyte injury drives proteinuria in lupus nephritis (LN). Targeting therapy against podocyte injury in LN is in demand. The E3 ubiquitin ligase WWP2 has context-dependent roles in renal tubulointerstitial injury and repair; however, since immune disorder-induced podocyte injury has distinct pathological foundations than tubulointerstitial pathology, WWP2's function in podocytes and LN remains unknown. Here we found that WWP2 protein levels significantly increased in the glomeruli of LN kidneys and were correlated with proteinuria in patients. Renal WWP2 knockdown alleviated, while its overexpression exacerbated proteinuria and podocyte injury in MRL/lpr mice. Podocyte-specific WWP2 deficiency protected against proteinuria in the NTS model. Mechanistically, multi-omics analysis revealed WWP2's association with systemic lupus erythematosus pathways and histone H2A. We identified WWP2 as a novel E3 ligase that monoubiquitylated H2A at K119 (ub-H2A). Ub-H2A levels increased in LN glomeruli, depended on WWP2, and mediated WWP2-aggravated podocyte injury. This effect involved alteration of actin dynamics via FAK signaling. Finally, a novel WWP2 inhibitor attenuated proteinuria in nephritic mice. In conclusion, the WWP2/ub-H2A axis promotes podocyte injury in LN by disrupting actin dynamics. Targeting this pathway represents a potential therapeutic strategy for LN.