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EMBO Rep ; 25(4): 2045-2070, 2024 Apr.
Article in English | MEDLINE | ID: mdl-38454159

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.


Subject(s)
Cytoskeletal Proteins , Infertility, Male , Teratozoospermia , Thiazoles , Animals , Humans , Male , Mice , Adaptor Proteins, Signal Transducing/genetics , Adaptor Proteins, Signal Transducing/metabolism , Dyneins/metabolism , HSC70 Heat-Shock Proteins/genetics , HSC70 Heat-Shock Proteins/metabolism , Infertility, Male/genetics , Infertility, Male/pathology , Molecular Chaperones/genetics , Molecular Chaperones/metabolism , Protein Folding , Semen/metabolism , Sperm Head/physiology , Spermatogenesis/genetics , Spermatozoa/metabolism , Teratozoospermia/metabolism , Teratozoospermia/pathology
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