Isoform-specific GSK3A activity is negatively correlated with human sperm motility.
In mouse and bovine sperm, GSK3 activity is inversely proportional to motility. Targeted disruption of the GSK3A gene in testis results in normal spermatogenesis, but mature sperm present a reduced motility, rendering male mice infertile. On the other hand, GSK3B testis-specific KO is fertile. Yet in human sperm, an isoform-specific correlation between GSK3A and sperm motility was never established. In order to analyze GSK3 function in human sperm motility, normospermic and asthenozoospermic samples from adult males were used to correlate GSK3 expression and activity levels with human sperm motility profiles. Moreover, testicular and sperm GSK3 interactomes were identified using a yeast two-hybrid screen and coimmunoprecipitation, respectively. An extensive in-silico analysis of the GSK3 interactome was performed. The results proved that inhibited GSK3A (serine phosphorylated) presents a significant strong positive correlation (r = 0.822, P = 0.023) with the percentage of progressive human sperm, whereas inhibited GSK3B is not significantly correlated with sperm motility (r = 0.577, P = 0.175). The importance of GSK3 in human sperm motility was further reinforced by in-silico analysis of the GSK3 interactome, which revealed a high level of involvement of GSK3 interactors in sperm motility-related functions. The limitation of techniques used for GSK3 interactome identification can be a drawback, since none completely mimics the physiological environment. Our findings prove that human sperm motility relies on isoform-specific functions of GSK3A within this cell. Given the reported relevance of GSK3 protein-protein interactions in sperm motility, we hypothesized that they stand as potential targets for male contraceptive strategies based on sperm motility modulation.
['Freitas|M J|MJ|', 'Silva|J V|JV|', 'Brothag|C|C|', 'Regadas-Correia|B|B|', 'Fardilha|M|M|', 'Vijayaraghavan|S|S|']
D000328:Adult D000818:Animals D053627:Asthenozoospermia D002417:Cattle D005298:Fertility D015870:Gene Expression D020869:Gene Expression Profiling D038362:Glycogen Synthase Kinase 3 D006801:Humans D007527:Isoenzymes D008297:Male D051379:Mice D010766:Phosphorylation D011485:Protein Binding D025941:Protein Interaction Mapping D011499:Protein Processing, Post-Translational D013081:Sperm Motility D013091:Spermatogenesis D013094:Spermatozoa D013737:Testis
sperm motility GSK3 interactome sperm biochemistry