Homeodomain-interacting protein kinase HIPK4 regulates phosphorylation of manchette protein RIMBP3 during spermiogenesis
Liu, X.; Zang, C.; Wu, Y.; Meng, R.; Chen, Y.; Jiang, T.; Wang, C.; Yang, X.; Guo, Y.; Situ, C.; Hu, Z.; Zhang, J.; Guo, X.
Journal of Biological Chemistry 298(9): 102327
ISSN/ISBN: 1083-351X PMID: 35931115 Accession: 080169997
Nonobstructive azoospermia (NOA) is the most serious form of spermatogenesis abnormalities in male infertility. Genetic factors are important to consider as elements leading to NOA. Although many pathogenic genes have been reported, the causative genes of NOA for many patients are still unknown. In this study, we found ten point mutations in the gene encoding homeodomain-interacting protein kinase 4 (HIPK4) in patients with NOA, and using in vitro studies we determined a premature termination point mutation (p. Lys490*, c.1468A>T) that can cause decreased expression of HIPK4. Our phosphoproteomic analysis of Hipk4-/- testes revealed phosphorylation of multiple proteins regulated by HIPK4 during spermiogenesis. We also confirmed that a substrate of HIPK4 with four down-regulated phosphorylation sites matching the xSPx motif is the known manchette-related protein RIMS-binding protein 3 (RIMBP3), which is required for sperm head morphogenesis. Therefore, we conclude HIPK4 regulates the phosphorylation of manchette protein RIMBP3 and plays essential roles in sperm head shaping and male fertility.