Abstract
The Cancer/Testis Antigen (CTA) genes comprise a group of genes whose expression under physiological conditions is restricted to the testis but is activated in many human cancers. Depending on the particular expression pattern, the CTA genes are speculated to play a role in spermatogenesis, but evidence is limited thus far. Here, we reported patients with a hemizygous nonsense mutation in cancer-testis antigen 55 (CT55) suffering from male infertility with extreme disruption in sperm production, morphology, and locomotion. Specifically, the insufficiency of sperm individualization, excessive residue of unnecessary cytoplasm, and defects in acrosome development were evident in the spermatozoa of the patients. Furthermore, mouse models with depletion of Ct55 showed accelerated infertility with age, mimicking the defects in sperm individualization, unnecessary cytoplasm removal, and meanwhile exhibiting the disrupted cumulus-oocyte complex penetration. Mechanistically, our functional experiments uncovered CT55 as a new autophagic manipulator to regulate spermatogenesis via selectively interacting with LAMP2 and GABARAP (which are key regulators in the autophagy process) and further fine-tuning their expression. Therefore, our findings revealed CT55 as a novel CTA gene involved in spermatogenesis due to its unprecedented autophagy activity.