Testis-specific serine kinase 3 is required for sperm morphogenesis and male fertility.

Autor: Nozawa K; Center for Drug Discovery, Baylor College of Medicine, Houston, Texas, USA.; Department of Pathology and Immunology, Baylor College of Medicine, Houston, USA., Garcia TX; Center for Drug Discovery, Baylor College of Medicine, Houston, Texas, USA.; Department of Pathology and Immunology, Baylor College of Medicine, Houston, USA.; Scott Department of Urology, Baylor College of Medicine, Houston, Texas, USA., Kent K; Center for Drug Discovery, Baylor College of Medicine, Houston, Texas, USA.; Department of Pathology and Immunology, Baylor College of Medicine, Houston, USA., Leng M; Mass Spectrometry Proteomics Core, Baylor College of Medicine, Houston, Texas, USA., Jain A; Mass Spectrometry Proteomics Core, Baylor College of Medicine, Houston, Texas, USA., Malovannaya A; Mass Spectrometry Proteomics Core, Baylor College of Medicine, Houston, Texas, USA.; Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, Texas, USA., Yuan F; Center for Drug Discovery, Baylor College of Medicine, Houston, Texas, USA.; Department of Pathology and Immunology, Baylor College of Medicine, Houston, USA., Yu Z; Center for Drug Discovery, Baylor College of Medicine, Houston, Texas, USA.; Department of Pathology and Immunology, Baylor College of Medicine, Houston, USA., Ikawa M; Department of Experimental Genome Research, Research Institute for Microbial Diseases, Osaka University, Suita, Japan.; The Institute of Medical Science, The University of Tokyo, Minato-ku, Japan., Matzuk MM; Center for Drug Discovery, Baylor College of Medicine, Houston, Texas, USA.; Department of Pathology and Immunology, Baylor College of Medicine, Houston, USA.
Jazyk: angličtina
Zdroj: Andrology [Andrology] 2023 Jul; Vol. 11 (5), pp. 826-839. Date of Electronic Publication: 2022 Nov 16.
DOI: 10.1111/andr.13314
Abstrakt: Background: The importance of phosphorylation in sperm during spermatogenesis has not been pursued extensively. Testis-specific serine kinase 3 (Tssk3) is a conserved gene, but TSSK3 kinase functions and phosphorylation substrates of TSSK3 are not known.
Objective: The goals of our studies were to understand the mechanism of action of TSSK3.
Materials and Methods: We analyzed the localization of TSSK3 in sperm, used CRISPR/Cas9 to generate Tssk3 knockout (KO) mice in which nearly all of the Tssk3 open reading frame was deleted (ensuring it is a null mutation), analyzed the fertility of Tssk3 KO mice by breeding mice for 4 months, and conducted phosphoproteomics analysis of male testicular germ cells.
Results: TSSK3 is expressed in elongating sperm and localizes to the sperm tail. To define the essential roles of TSSK3 in vivo, heterozygous (HET) or homozygous KO male mice were mated with wild-type females, and fertility was assessed over 4 months; Tssk3 KO males are sterile, whereas HET males produced normal litter sizes. The absence of TSSK3 results in disorganization of all stages of testicular seminiferous epithelium and significantly increased vacuolization of germ cells, leading to dramatically reduced sperm counts and abnormal sperm morphology; despite these histologic changes, Tssk3 null mice have normal testis size. To elucidate the mechanisms causing the KO phenotype, we conducted phosphoproteomics using purified germ cells from Tssk3 HET and KO testes. We found that proteins implicated in male infertility, such as GAPDHS, ACTL7A, ACTL9, and REEP6, showed significantly reduced phosphorylation in KO testes compared to HET testes, despite unaltered total protein levels.
Conclusions: We demonstrated that TSSK3 is essential for male fertility and crucial for phosphorylation of multiple infertility-related proteins. These studies and the pathways in which TSSK3 functions have implications for human male infertility and nonhormonal contraception.
(© 2022 The Authors. Andrology published by Wiley Periodicals LLC on behalf of American Society of Andrology and European Academy of Andrology.)
Databáze: MEDLINE
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