State Key Laboratory of Molecular Biology, Shanghai Key Laboratory of Molecular Andrology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China.
Department of Urology, Huashan Hospital, Fudan University, Shanghai, China.
J Mol Cell Biol. 2018 Dec 1;10(6):503-514. doi: 10.1093/jmcb/mjy024.
Infertility is a severe public health problem worldwide that prevails up to 15% in reproductive-age couples, and male infertility accounts for half of total infertility. Studies on genetically modified animal models have identified lots of genes involved in the pathogenesis of male infertility. The underlying causes, however, remain largely unclear. In this study, we provide evidence that EMC10, one subunit of endoplasmic reticulum (ER) membrane protein complex (EMC), is required for male fertility. EMC10 is significantly decreased in spermatozoa from patients with asthenozoospermia and positively associated with human sperm motility. Male mice lacking Emc10 gene are completely sterile. Emc10-null spermatozoa exhibit multiple defects including abnormal morphology, decreased motility, impaired capacitation, and impotency of acrosome reaction, thereby which are incapable of fertilizing intact or ZP-free oocytes. However, intracytoplasmic sperm injection could rescue this defect caused by EMC10 deletion. Mechanistically, EMC10 deficiency leads to inactivation of Na/K-ATPase, in turn giving rise to an increased level of intracellular Na+ in spermatozoa, which contributes to decreased sperm motility and abnormal morphology. Other mechanistic investigations demonstrate that the absence of EMC10 results in a reduction of HCO3- entry and subsequent decreases of both cAMP-dependent protein kinase A substrate phosphorylation and protein tyrosine phosphorylation. These data demonstrate that EMC10 is indispensable to male fertility via maintaining sperm ion balance of Na+ and HCO3-, and also suggest that EMC10 is a promising biomarker for male fertility and a potential pharmaceutical target to treat male infertility.
不育症是一个严重的全球性公共卫生问题，在育龄夫妇中患病率高达 15%，其中男性不育症占总不育症的一半。对基因修饰动物模型的研究已经确定了许多与男性不育症发病机制相关的基因。然而，其根本原因在很大程度上仍不清楚。在这项研究中，我们提供了证据表明，内质网（ER）膜蛋白复合物（EMC）的一个亚基 EMC10，是精子发生所必需的。在弱精症患者的精子中，EMC10 的含量明显降低，并且与人类精子的运动能力呈正相关。缺乏 Emc10 基因的雄性小鼠完全不育。Emc10 缺失的精子表现出多种缺陷，包括形态异常、运动能力下降、获能受损和顶体反应无能，因此无法使完整或无 ZP 的卵子受精。然而，胞质内精子注射可以挽救 EMC10 缺失引起的缺陷。从机制上讲，EMC10 缺乏导致 Na/K-ATP 酶失活，进而导致精子内 Na+水平升高，导致精子运动能力下降和形态异常。其他机制研究表明，EMC10 的缺失导致 HCO3-进入减少，继而导致 cAMP 依赖性蛋白激酶 A 底物磷酸化和蛋白酪氨酸磷酸化减少。这些数据表明，EMC10 通过维持精子的 Na+和 HCO3-离子平衡，对男性生育力是不可或缺的，并且表明 EMC10 是男性生育力的一个有前途的生物标志物，也是治疗男性不育症的潜在药物靶点。
