Retinoic Acid Modulates the Subcellular Localization of Small Ubiquitin-Related Modifier-2/3 (SUMO-2/3) in the Testis

Covalent attachment of small ubiquitin-related modifier (SUMO) to target proteins is an important posttranslational mechanism controlling diverse cellular functions. Recently, hypoor hyper-sumoylation by SUMO-2/3 was shown to play a crucial role in male reproduction. However, the regulation of SUMO-2/3 in the testis remains unknown. Here, we report that the subcellular localization of SUMO-2/3 changes during testicular development. SUMO-2/3 was mainly found localized in the nucleus of Sertoli cells and gonocytes early in testicular development, but the localization shifted to the cytoplasm in Sertoli and germ cells after meiotic initiation. This change in the subcellular localization was mimicked both in testes of postnatal day 10 (P10) rats injected with all-trans retinoic acid (ATRA) and in organ cultures of testes from P10 rats treated with ATRA. These results suggest that retinoic acid might have a role in controlling the subcellular localization of SUMO-2/3. Moreover, treatment of Sertoli cells with a retinoic acid receptor alpha (RARA)-specific agonist changed the subcellular localization of SUMO-2/3 from the nucleus to the cytoplasm. Furthermore, disruption of the retinoic acid receptor alpha (Rara) gene in the testis resulted in alteration of SUMO-2/3 subcellular localization, indicating that its protein RARA might have a role in the nuclear trafficking of SUMO-2/3. Because many SUMO target proteins are usually modified en masse after a biological stimulus, our results suggest that dysregulation of SUMO-2/3 subcellular localization could easily be a pleiotropic contributing factor that can cause a male sterility phenotype in Rara-null mice.