Uncovering the protein complex critical to male fertility

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.