UBL7 is indispensable for spermiogenesis through protecting critical factors from excessive degradation by proteasomes

Spermiogenesis is a tightly regulated process to produce mature sperm cells. The ubiquitin-proteasome system (UPS) plays a crucial role in controlling protein half-life and is essential for spermiogenesis. Recently, proteins containing ubiquitin-like domains and ubiquitin-associated domains (UBL-UBA proteins) have emerged as novel regulators within the UPS. In this study, we demonstrate that UBL7, a testis-enriched UBL-UBA protein, is indispensable for sperm formation. Deficiency of UBL7 leads to severe malformations of both the sperm tail and head. Mechanistically, UBL7 interacts with the valosin-containing protein (VCP) complex and proteasomes, and shuttles substrates between them. Notably, UBL7 slows down the degradation rates of substrates involved in endoplasmic reticulum-associated degradation (ERAD) within cells. Through a two-step immunoprecipitation method, we identify several essential factors in spermatids that are protected by UBL7, including factors involved in the development of manchette (such as IFT88), head-tail coupling apparatus (such as SPATA20) and cytoplasmic droplets (such as HK1). In summary, our findings highlight UBL7 as a guardian that protects crucial factors from excessive degradation and thereby ensures successful spermiogenesis.