COPS5 is Essential for Sertoli Cell Function and Male Fertility in Mice

Niu, C.; Li, T.; Li, W.; Yap, Y. T.; Huang, Q.; Jiang, L.; Dhikhirullahi, O.; Miciuda, A.; Faddoul, E.; Song, S.; Griswold, M. D.; Zhang, Z.

doi:10.64898/2025.12.19.695357

bioRxiv · 10.64898/2025.12.19.695357

COPS5 is Essential for Sertoli Cell Function and Male Fertility in Mice

Niu, C.·Li, T.·Li, W.·Yap, Y. T.·Huang, Q.·Jiang, L.·Dhikhirullahi, O.·Miciuda, A.·Faddoul, E.·Song, S.·Griswold, M. D.·Zhang, Z.

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Abstract

The COP9 signalosome subunit 5 (COPS5) is a multifunctional protein that regulates ubiquitin-dependent processes. Global knockout of Cops5 is embryonically lethal, and while it is known to be vital in germ cells and testicular smooth muscle, its function in Sertoli cells, the key somatic supporters of spermatogenesis, remains entirely unknown. This study investigates the critical role of COPS5 within Sertoli cells. Using Sertoli cell-specific Cops5 knockout mouse models, we demonstrate that COPS5 is essential for maintaining male fertility. Sertoli-specific Cops5 ablation resulted in age-dependent male infertility, despite normal initial development. Mutants exhibited progressive testicular atrophy, oligoasthenospermia, and significantly reduced testis weight. Histology showed vacuolated, disorganized tubules devoid of germ cells and sperm. Crucially, COPS5 loss disrupted Sertoli cell polarity, evidenced by aberrant cytoplasmic mislocalization of the nuclear marker WT1 and detachment from the basement membrane. Integrity of the blood-testis barrier (BTB) was severely compromised, with discontinuous and punctate expression of the tight junction adaptor ZO-1. Intercellular communication was also impaired, shown by a stark reduction in Connexin 43 gap junction signals. Our findings establish that COPS5 is an indispensable intrinsic regulator of Sertoli cell function. Its loss disrupts cell polarity, BTB architecture, and gap junction communication, leading to failed support of spermatogenesis and consequently infertility. This work defines a novel and critical somatic function for COPS5 in male reproduction. We conclude that COPS5 is intrinsically required in Sertoli cells to maintain their polarity and BTB function, which are foundational for supporting germ cell development and ensuring male fertility. This identifies COPS5 as a novel, essential regulator within the testicular somatic compartment.

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Niu, C., Li, T., Li, W., Yap, Y. T., Huang, Q., Jiang, L., Dhikhirullahi, O., Miciuda, A., Faddoul, E., Song, S., Griswold, M. D., Zhang, Z.. 2025-12-22. COPS5 is Essential for Sertoli Cell Function and Male Fertility in Mice. https://doi.org/10.64898/2025.12.19.695357

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