%0 Journal Article
%T BAG5 regulates HSPA8-mediated protein folding required for sperm head-tail coupling apparatus assembly.
%A Gan S
%A Zhou S
%A Ma J
%A Xiong M
%A Xiong W
%A Fan X
%A Liu K
%A Gui Y
%A Chen B
%A Zhang B
%A Wang X
%A Wang F
%A Li Z
%A Yan W
%A Ma M
%A Yuan S
%J EMBO Rep
%V 25
%N 4
%D 2024 Apr 7
%M 38454159
%F 9.071
%R 10.1038/s44319-024-00112-x
%X 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.