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

Tianyi Yuan, Jiajun Yang, Dan Xu, Huiqi Li, Wanping Min and Fengchao Wang ()
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Tianyi Yuan: Chinese Academy of Medical Sciences
Jiajun Yang: National Institute of Biological Sciences
Dan Xu: National Institute of Biological Sciences
Huiqi Li: National Institute of Biological Sciences
Wanping Min: National Institute of Biological Sciences
Fengchao Wang: Chinese Academy of Medical Sciences

Nature Communications, 2025, vol. 16, issue 1, 1-18

Abstract: Abstract 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 IFT140), head-tail coupling apparatus (such as SPATA20) and cytoplasmic droplets (such as HK1 and SLC2a3). In summary, our findings highlight UBL7 as a guardian that protects crucial factors from excessive degradation and thereby ensures successful spermiogenesis.

Date: 2025
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DOI: 10.1038/s41467-025-59209-z

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