PAK4 promotes the cytoskeletal organization and meiotic maturation via phosphorylating DDX17 in oocyte

PAK4 has been widely reported to function in somatic cells. However, its role and the underlying mechanisms in meiotic oocytes are largely unknown. Here, we show that PAK4 deficiency significantly disrupts maturational progression and meiotic apparatus in mouse oocytes. Furthermore, based on the kinase substrate binding preference and systematic functional screening, our mechanistic investigation demonstrated that PAK4 promotes cytoskeletal organization and oocyte maturation through phosphorylating serine 597 on DDX17. Of note, we identified a marked reduction of PAK4 protein in oocytes from diabetic mice. Importantly, ectopic expression of hyperphosphorylation-mimicking DDX17 mutant (DDX17-S597D) partly prevented the meiotic defects in these diabetic oocytes, indicating that the decreased phosphorylation of DDX17 due to PAK4 insufficiency is responsible for the impaired oocyte quality. In sum, these findings unveil the pivotal role of PAK4 in oocyte development and indicate a novel mechanism controlling meiotic progression and structure.