SEL1L regulates ER homeostasis in Sertoli cells but is dispensable for their function.

Endoplasmic reticulum (ER)-associated protein degradation (ERAD) plays a vital role in maintaining ER homeostasis by degrading misfolded ER proteins. The SEL1L-HRD1 complex, the most evolutionarily conserved branch of ERAD, has been implicated in various physiological processes in both mice and humans, including cellular stress responses, immune function, and development. However, its role in Sertoli cells, which are critical for supporting spermatogenesis, remains unexplored. Here, we show that Sertoli cell SEL1L is not essential for their function or spermatogenesis. SEL1L and HRD1 proteins are expressed in Sertoli cells, and the deletion of SEL1L in Sertoli cells reduces HRD1 protein levels and impairs ERAD function. This leads to elevated ER stress responses and increased expression of ER chaperones, suggesting a potential compensatory adaptation to maintain ER homeostasis. Despite these changes, Sertoli cell-specific Sel1L deletion does not disrupt testicular histology, sperm count, or male fertility. These findings reveal the adaptation of Sertoli cells to SEL1L and ERAD dysfunction and highlight their ability to sustain spermatogenesis under ER stress.