The PSMA8 subunit of the spermatoproteasome is essential for proper meiotic exit and mouse fertility.

The ubiquitin proteasome system regulates meiotic recombination in yeast through its association with the synaptonemal complex, a 'zipper'-like structure that holds homologous chromosome pairs in synapsis during meiotic prophase I. In mammals, the proteasome activator subunit PA200 targets acetylated histones for degradation during somatic DNA double strand break repair and during histone replacement during spermiogenesis. We investigated the role of the testis-specific proteasomal subunit alpha 4s (PSMA8) during spermatogenesis, and found that PSMA8 was localized to and dependent on the central region of the synaptonemal complex. Accordingly, synapsis-deficient mice show delocalization of PSMA8. Moreover, though Psma8-deficient mice are proficient in meiotic homologous recombination, there are alterations in the proteostasis of several key meiotic players that, in addition to the known substrate acetylated histones, have been shown by a proteomic approach to interact with PSMA8, such as SYCP3, SYCP1, CDK1 and TRIP13. These alterations lead to an accumulation of spermatocytes in metaphase I and II which either enter massively into apoptosis or give rise to a low number of aberrant round spermatids that apoptose before histone replacement takes place. Author summary Proteins within the cells that are unnecessary or damaged are degraded by a large protein complex named the proteasome. The proteins to be degraded are marked by a small protein called ubiquitin. The addition of a small modification (acetyl group) to some proteins also promotes their degradation by the proteasome. Proteasomal degradation of proteins is an essential mechanism for many developmental programs including gametogenesis, a process whereby a diploid cell produces a haploid cell or gamete (sperm or egg). The mechanism by which this genome reduction occurs is called meiosis. Here, we report the study of a protein, named PSMA8 that is specific for the testis proteasome in vertebrates. Using the mouse as a model, we show that loss of PSMA8 leads to infertility in males. By co-immunoprecipitation-coupled mass spectroscopy we identified a large list of novel PSMA8 interacting proteins. We focused our functional analysis on several key meiotic proteins which were accumulated such as SYCP3, SYCP1, CDK1 and TRIP13 in addition to the known substrate of the spermatoproteasome, the acetylated histones. We suggest that the altered accumulation of these important proteins causes a disequilibrium of the meiotic division that produces apoptotic spermatocytes in metaphase I and II and also early spermatids that die soon after reaching this stage.