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

Author:

Gan ShimingORCID,Zhou ShuminORCID,Ma Jinzhe,Xiong Mengneng,Xiong Wenjing,Fan Xu,Liu Kuan,Gui Yiqian,Chen Bei,Zhang Beibei,Wang Xiaoli,Wang Fengli,Li ZheanORCID,Yan Wei,Ma Meisheng,Yuan ShuiqiaoORCID

Abstract

AbstractTeratozoospermia 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.

Funder

MOST | National Natural Science Foundation of China

MOE | Fundamental Research Funds for the Central Universities

Basic Research Support Program of Huazhong University of Science and Technology

Publisher

Springer Science and Business Media LLC

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