Abstract
Spermatogenesis is a highly specialized process that requires extensive endoplasmic reticulum (ER)-mediated protein biogenesis in the beginning, followed by ER degradation toward the end. As a principal ER protein degradation and quality control machinery, the role of ER-associated protein degradation (ERAD) in spermatogenesis has never been explored. Here, we investigate the function of SEL1L-HRD1 ERAD, the most conserved mammalian ERAD, in spermatogenesis. Serendipitously, we discovered a dissociation of SEL1L and HRD1 activity during this process. Unlike SEL1L, HRD1 is essential for spermatogenesis. Deletion of Hrd1, but not Sel1L, in male germ cells leads to male infertility, defects in sperm morphogenesis and differentiation, and disrupted ER homeostasis. Mechanistically, we found, for the first time, that SEL1L is not required for HRD1 stability or ERAD activity in spermatocytes, suggesting a SEL1L-independent function of HRD1 and the potential involvement of testis-specific HRD1 cofactors. Together, this study highlights a surprising function and molecular mechanism of ERAD during spermatogenesis, warranting further investigation into ERAD in germ cell differentiation.
