BAG5 regulates HSPA8-mediated protein folding required for sperm head-tail coupling apparatus assembly.

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. © 2024. The Author(s).

Citation

Shiming Gan, Shumin Zhou, Jinzhe Ma, Mengneng Xiong, Wenjing Xiong, Xu Fan, Kuan Liu, Yiqian Gui, Bei Chen, Beibei Zhang, Xiaoli Wang, Fengli Wang, Zhean Li, Wei Yan, Meisheng Ma, Shuiqiao Yuan. BAG5 regulates HSPA8-mediated protein folding required for sperm head-tail coupling apparatus assembly. EMBO reports. 2024 Apr;25(4):2045-2070

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PMID: 38454159

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