Protein phosphatase 2A (PP2A) function in male germ cells and its importance for male fertility

Infertility is a common issue that affects approximately 30 million men worldwide, most often resulting from defects during spermatogenesis, a complex cellular differentiation process allowing the formation of spermatozoa. During spermatogenesis, a large number of proteins involved in sperm production are phosphorylated, mainly on serine and threonine residues. As recently shown, this phosphorylation process is essential for male fertility. Protein phosphorylation depends on a balance between kinase and phosphatase activity, and although the kinases involved are relatively well characterized, much less is known about the presence and role of serine/threonine phosphatases within male germ cells. The aim of this review is to highlight the importance of protein phosphatase 2A (PP2A) in male fertility through direct expression of several PP2A subunits in male germ cells. First, the review will provide current knowledge on PP2A structure and regulation. Then, the importance of PP2A for spermatogenesis will be illustrated by the description of gene mutations and deletions recently identified in PP2A that result in male infertility, both in humans and mice. The review will also provide information on the level and stage of expression of PP2A subunits and endogenous inhibitors in human male germ cells, indicative of their dynamic regulation throughout spermatogenesis. Finally, the review will explore the involvement of PP2A beyond spermatogenesis during sperm maturation processes. Overall, this review highlights the critical functions of PP2A in male germ cells, reinforcing the importance of investigating the potential pathogenic deregulation of PP2A activity in cases of human male infertility.