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.
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The data analysed during this study are included in this published article and the Supplementary data files. Additional supporting data are available from the corresponding authors upon reasonable request.
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Acknowledgements
We thank to the patients, their family members, and the normal controls for their support and contribution in this study. We thank to the Analytical and Testing Center of Sichuan University for the morphology characterization and the authors would be grateful to Guiping Yuan and Yi He for their help of TEM and SEM images.
Funding
This work was supported by The National Natural Science Foundation of China (82000514).
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YS designed and supervised the study experiments. Yihong Y, YW, QS and TZ collected the data and conducted the clinical evaluations of the participants. GZ and CJ performed most of the experiments and analyzed the data. Yanting Y, SD, Yushang Y, LY and ML participated in the experiments including immunofluorescence, western blotting and cell culture. HZ and XZ generated the CRISPR mice and conducted the fertility assessment. YS wrote the manuscript. All authors revised and approved the article.
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All the animal experiments were performed in accordance with the recommendation of the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health and the animal experiments were approved by the Experimental Animal Management and Ethics Committee of West China Second University Hospital (IACUC no. 2021(070)). For human participants, the study was approved by the Ethical Review Board of West China Second University Hospital (IRB no. 2019(040)), Sichuan University.
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Zhang, G., Jiang, C., Yang, Y. et al. Deficiency of cancer/testis antigen gene CT55 causes male infertility in humans and mice. Cell Death Differ 30, 500–514 (2023). https://doi.org/10.1038/s41418-022-01098-6
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DOI: https://doi.org/10.1038/s41418-022-01098-6
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