RNF187 Facilitates Proliferation and Migration of Human Spermatogonial Stem Cells Through WDR77 Polyubiquitination

ABSTRACT The E3 ubiquitin ligase RNF187, also known as RING domain AP1 coactivator‐1, is a member of the RING finger family. RNF187 is indispensable for the proliferation and migration of GC‐1 cells derived from mouse spermatogonia and GC‐2 cells derived from spermatocytes. However, it remains unclear whether RNF187 plays a crucial role in the self‐renewal and migration of human spermatogonial stem cells (SSCs). In this study, we observed a positive correlation between RNF187 expression and the proliferation and migration of human SSCs. Through co‐immunoprecipitation and mass spectrometry analyses, we identified WD repeat‐containing protein 77 (WDR77) as an interacting partner of RNF187. Specifically, RNF187 recognises the K118 site of WDR77 through lysine 48‐linked polyubiquitination, subsequently mediating its degradation via the ubiquitin‐proteasome system (UPS). Further studies have revealed that decreased expression of WDR77 diminishes the symmetric dimethylation at H4R3 (H4R3me2s) catalysed by its interacting protein, the arginine methyltransferase PRMT5. This, in turn, relieves the transcriptional repression of early growth response protein 1 (EGR1), a positive regulator for human SSC maintenance. In conclusion, this study has unveiled a pivotal role for RNF187 in the proliferation and migration of human SSCs. This may provide a promising strategy for addressing non‐obstructive azoospermia (NOA) caused by SSC dysfunction.