Tudor-SN, a novel COPII-associated protein, promotes mouse reproduction by regulating the secretion of gonadotropin

Introduction Coat protein complex II (COPII) vesicles mediate cargo transport from the endoplasmic reticulum (ER) to the Golgi apparatus. The composition and assembly of COPII vesicles depend on the transported cargo and are regulated by various accessory factors. However, the mechanisms underlying this variability remain incompletely understood. Methods Here, we identify Tudor-SN as a novel COPII-associated protein and investigate its role in regulating reproductive development in mice by controlling gonadotropin secretion. We generated global and gonadotrope-specific Tudor-SN knockout mice and examined gonadotropin synthesis, secretion, and COPII assembly using biochemical, imaging, and functional assays. Results Tudor-SN is physiologically expressed in the adenohypophysis. Global or gonadotrope-specific knockout of Tudor-SN resulted in a phenotype resembling hypogonadotropic hypogonadism, characterized by reduced fertility, underdevelopment of gonadal organs, and decreased sex hormone secretion. Notably, Tudor-SN ablation did not affect gonadotropin synthesis but reduced the secretion of these hormones. Mechanistically, Tudor-SN physically binds to the initiator protein Sar1a and the scaffold protein Sec13 of COPII vesicles to facilitate their assembly. Tudor-SN deficiency disrupted Sar1a–Sec23 complex formation, impairing COPII vesicle biogenesis and gonadotropin trafficking from the ER. Discussion Our findings reveal that Tudor-SN is a critical regulator of gonadotropin secretion by promoting the initiation of COPII vesicle assembly, thereby linking a cellular role of Tudor-SN to a physiological function in promoting reproductive development in mice.