Yuan Lu, Ge Tingting, Yang Ling, Xu Wenhua, Li Guanghua, Xu Linwei, Zhao Yichun, Cheng Xu, Lu Wenting, Meng Shiqi, Zhao Jieyu, Yang Fan, Niu Changmin, Zheng Ying
Faculty of Medicine, Yangzhou University, Yangzhou, Jiangsu, China.
School of Nursing, Yangzhou University, Yangzhou, Jiangsu, China.
Commun Biol. 2025 Aug 9;8(1):1191. doi: 10.1038/s42003-025-08644-1.
In male reproduction, spermatogenesis and sperm maturation are critical for the production of normal sperm and offspring, yet the underlying molecular mechanisms remain largely elusive. Tex38 is a testis-enriched gene, and its deficiency results in oligoasthenoteratospermia (OAT) with aberrant epididymis, leading to male infertility in mice. Tex38 knockout (KO) sperm primarily exhibited neck bending deformities and functional abnormalities, including impaired fertilization. Proteomic analysis identified ADAM3 and its maturation-associated chaperones (CALR3, CLGN, and PDILT) as the most significantly altered proteins among the differentially expressed proteins (DEPs) in both sperm and epididymis of Tex38 knockout mice. GO analysis revealed that DEPs were primarily involved in sperm morphogenesis, motility, and fertilization. ARRDC5 was identified as a novel interacting protein of TEX38, and its deletion resulted in similar male infertility phenotypes as Tex38 deletion. Immunoprecipitation-mass spectrometry identified TEX38 and ARRDC5 interact with CLGN and PDILT. The interactions among TEX38, ARRDC5, PDILT, and CLGN were found to affect ADAM3 maturation, resulting in the failure of both Tex38 and Arrdc5 sperm to migrate to the oviduct. Overall, these findings establish TEX38 as an essential regulator of mammalian ADAM3-related migration, sperm formation, energy metabolism (ATP generation), sperm-egg binding and fertilization. TEX38 represents a potential target for diagnosis and treatment of male infertility and male contraception.
在雄性生殖过程中，精子发生和精子成熟对于正常精子的产生以及后代繁衍至关重要，但其潜在的分子机制仍 largely 难以捉摸。Tex38 是一种睾丸富集基因，其缺失会导致伴有附睾异常的少弱畸精子症（OAT），进而致使小鼠雄性不育。Tex38 基因敲除（KO）的精子主要表现出颈部弯曲畸形和功能异常，包括受精受损。蛋白质组学分析确定 ADAM3 及其成熟相关伴侣蛋白（CALR3、CLGN 和 PDILT）是 Tex38 基因敲除小鼠精子和附睾中差异表达蛋白（DEP）中变化最为显著的蛋白质。基因本体（GO）分析表明，DEP 主要参与精子形态发生、运动和受精过程。ARRDC5 被鉴定为 TEX38 的一种新型相互作用蛋白，其缺失导致与 Tex38 缺失相似的雄性不育表型。免疫沉淀 - 质谱分析确定 TEX38 和 ARRDC5 与 CLGN 和 PDILT 相互作用。研究发现 TEX38、ARRDC5、PDILT 和 CLGN 之间的相互作用会影响 ADAM3 的成熟，导致 Tex38 和 Arrdc5 基因敲除的精子均无法迁移至输卵管。总体而言，这些研究结果确立了 TEX38 作为哺乳动物 ADAM3 相关迁移、精子形成、能量代谢（ATP 生成）、精卵结合及受精的关键调节因子。TEX38 代表了男性不育诊断和治疗以及男性避孕的一个潜在靶点。
