PDF(Pubmed)
Abstract：
Teratozoospermia is a significant cause of male infertility, but the pathogenic mechanism of acephalic spermatozoa syndrome (ASS), one of the most severe teratozoospermia, remains elusive. We previously reported Spermatogenesis Associated 6 (SPATA6) as the component of the sperm head-tail coupling apparatus (HTCA) required for normal assembly of the sperm head-tail conjunction, but the underlying molecular mechanism has not been explored. Here, we find that the co-chaperone protein BAG5, expressed in step 9-16 spermatids, is essential for sperm HTCA assembly. BAG5-deficient male mice show abnormal assembly of HTCA, leading to ASS and male infertility, phenocopying SPATA6-deficient mice. In vivo and in vitro experiments demonstrate that SPATA6, cargo transport-related myosin proteins (MYO5A and MYL6) and dynein proteins (DYNLT1, DCTN1, and DNAL1) are misfolded upon BAG5 depletion. Mechanistically, we find that BAG5 forms a complex with HSPA8 and promotes the folding of SPATA6 by enhancing HSPA8\'s affinity for substrate proteins. Collectively, our findings reveal a novel protein-regulated network in sperm formation in which BAG5 governs the assembly of the HTCA by activating the protein-folding function of HSPA8.
摘要：
畸形精子症是男性不育的重要原因,但脑端精子综合征（ASS）的致病机制，最严重的畸形精子症之一,仍然难以捉摸。我们先前报道了精子发生相关6（SPATA6）作为精子头-尾连接正常组装所需的精子头-尾耦合装置（HTCA）的组成部分，但是潜在的分子机制还没有被探索。这里,我们发现，在步骤9-16精子细胞中表达的共同伴侣蛋白BAG5，是精子HTCA组装所必需的。BAG5缺陷的雄性小鼠显示HTCA的异常组装，导致ASS和男性不育，表型复制SPATA6缺陷小鼠。体内和体外实验表明，SPATA6，与货物运输相关的肌球蛋白蛋白（MYO5A和MYL6）和动力蛋白（DYNLT1，DCTN1和DNAL1）在BAG5耗尽后发生错误折叠。机械上,我们发现BAG5与HSPA8形成复合物，并通过增强HSPA8对底物蛋白的亲和力来促进SPATA6的折叠。总的来说，我们的发现揭示了精子形成中一种新的蛋白质调节网络，其中BAG5通过激活HSPA8的蛋白质折叠功能来控制HTCA的组装。
