{Reference Type}: Journal Article
{Title}: BAG5 regulates HSPA8-mediated protein folding required for sperm head-tail coupling apparatus assembly.
{Author}: Gan S;Zhou S;Ma J;Xiong M;Xiong W;Fan X;Liu K;Gui Y;Chen B;Zhang B;Wang X;Wang F;Li Z;Yan W;Ma M;Yuan S;
{Journal}: EMBO Rep
{Volume}: 25
{Issue}: 4
{Year}: 2024 Apr 7
{Factor}: 9.071
{DOI}: 10.1038/s44319-024-00112-x
{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.