ASB1 engages with ELOB to facilitate SQOR ubiquitination and H2S homeostasis during spermiogenesis

Abstract

Male infertility, frequently driven by oxidative stress, impacts half of infertile couples globally. Despite its significance, the precise mechanisms governing this process remain elusive. In this study, we demonstrate that ASB1, the substrate recognition subunit of a ubiquitin ligase, is highly expressed in the mouse testis. Mice lacking the Asb1 gene exhibit severe fertility impairment, characterized by oligoasthenoteratozoospermia. Subsequent investigations unveiled that Asb1 knockout (Asb1-KO) mice encountered excessive oxidative stress and decreased hydrogen sulfide (H₂S) levels in their testes, and severe sperm DNA damage. Notably, the compromised fertility and sperm quality in Asb1-KO mice was significantly ameliorated by administering NaHS, a H₂S donor. Mechanistically, ASB1 interacts with ELOB to induce the instability of sulfide-quinone oxidoreductase (SQOR) by enhancing its K48-linked ubiquitination on residues K207 and K344, consequently triggering proteasomal degradation. This process is crucial for preserving H₂S homeostasis and redox balance. Overall, our findings offer valuable insights into the role of ASB1 during spermiogenesis and propose H₂S supplementation as a promising therapeutic approach for oxidative stress-related male infertility.

Keywords: ASB1; Hydrogen sulfide; Oxidative stress; Polyubiquitination; Spermiogenesis.