Uncovering the protein complex critical to male fertility

Osaka, Japan – The human body is full of checks and balances that ensure correct growth, development, and function of all our different systems. Now, researchers from Japan have reported a newly discovered protein interaction that regulates sperm development.

In a study to be published soon in PNAS, a multi-institutional research team led by Osaka University has revealed that the interaction between two specific proteins is crucial for ensuring that sperm cells develop properly.

Sperm formation is a highly complex process that involves many changes to the cell structure, such as shrinking of the nucleus, generation of a sperm tail, and remodeling of the sperm head. Disrupting this process at any point can result in nonfunctional sperm and male infertility.

“Abnormal sperm formation impairs their ability to fertilize egg cells,” explains Yuki Kaneda, lead author of the study. “While some genes that are essential for spermiogenesis have been identified, there is much that remains unknown about the molecular mechanisms of this intricate process.”

To explore factors that may affect sperm formation, the researchers disrupted the expression of TEX38 (a protein that is found primarily in the testes) in mice and found that the heads of the resulting sperm were bent backwards, causing infertility. Next, they investigated why deleting this protein had such a strong effect by looking at the other proteins that it interacts with.

“The results were striking,” says Masahito Ikawa, senior author. “We found that TEX38 interacts with ZDHHC19; deleting either protein resulted in the same sperm deformity, and if one of the proteins was absent, the other was expressed at much lower levels.”

ZDHHC19 is an enzyme that adds lipids to proteins in a process called S-palmitoylation. Importantly, ZDHHC19 carries out S-palmitoylation of ARRDC5, a protein known to be crucial for sperm development. When ZDHHC19 was prevented from making this lipid modification, sperm were deformed in the same way that they were when TEX38 expression was disrupted—i.e., excess cytoplasm was not removed from the sperm head.

“Our findings show that TEX38 and ZDHHC19 form a complex in developing sperm. This complex regulates S-palmitoylation of the proteins that are essential for generating functional sperm with the correct morphology,” says Kaneda.

Given that sperm shape and structure are key elements of sperm function, the findings from this study provide important insight into the causes of male infertility. This could help to develop male contraceptives that prevent lipid modification, thereby impairing sperm development and reducing or preventing fertility.

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The article, “TEX38 localizes ZDHHC19 to the plasma membrane and regulates sperm head morphogenesis in mice,” was published in PNAS at DOI: https://doi.org/10.1073/pnas.2417943122

About Osaka University
Osaka University was founded in 1931 as one of the seven imperial universities of Japan and is now one of Japan's leading comprehensive universities with a broad disciplinary spectrum. This strength is coupled with a singular drive for innovation that extends throughout the scientific process, from fundamental research to the creation of applied technology with positive economic impacts. Its commitment to innovation has been recognized in Japan and around the world. Now, Osaka University is leveraging its role as a Designated National University Corporation selected by the Ministry of Education, Culture, Sports, Science and Technology to contribute to innovation for human welfare, sustainable development of society, and social transformation.
Website: https://resou.osaka-u.ac.jp/en