Exploring QRICH2 as a potential male contraceptive target

Today, male contraceptive options remain limited to condoms and vasectomy, highlighting the urgent need for alternative methods. In this context, discovering and characterizing reproductive-tract-specific proteins that can be targeted by natural or chemical molecules is of particular interest. Recent studies on the sperm protein glutamine-rich protein 2 (QRICH2) show that it could represent a promising candidate. Indeed, it has been genetically confirmed to be essential for male fertility in mice, bulls, and humans, with gene knockout and loss-of-function mutations leading to defective sperm and complete infertility without evident accompanying symptoms. However, information on human QRICH2 remains limited. In this study, we aimed to better characterize human QRICH2 to assess its potential as a target for male contraceptive development. Using mass spectrometry, we assessed which of the QRICH2 isoforms described in databases might be expressed in human sperm. Through in silico analyses, we showed that QRICH2 has no paralogs in humans, and is conserved across mammals, particularly in a region containing two functional domains, suggesting their importance for QRICH2 function. Finally, using immunodetection methods and proteomic dataset analyses, we investigated the tissue specificity of QRICH2 by examining its protein expression across 12 human organs. Our results show that QRICH2 is restricted to the testes, where it localizes to different cellular compartments throughout spermatogenesis, and acts as a cytoskeletal component in mature sperm, both in the head and flagellum. We conclude that QRICH2 represents a promising candidate for further investigation as a potential target for male contraception and we propose different strategies that could be explored for its inhibition.