UCHL3-mediated proteasomal degradation of GOPC drives microcystin-LR-induced acrosomal dysgenesis.

Growing evidence links environmental exposure to microcystin-leucine-arginine (MC-LR) with declining male fertility, yet its molecular pathogenesis remains poorly understood. In this study, we observed that MC-LR disrupted acrosome biogenesis, a critical process for sperm function. Mechanistically, MC-LR induced proteasomal degradation of Golgi-associated PDZ- and coiled-coil motif-containing protein (GOPC), a key acrosome assembly protein, by disrupting its ubiquitin homeostasis. This degradation resulted from dual inhibition of MC-LR on the deubiquitinase ubiquitin carboxyl terminal hydrolase L3 (UCHL3). MC-LR directly bound to catalytic domain of UCHL3, obstructing its interaction with GOPC and inhibiting its enzymatic activity. MC-LR was also found to suppresses UCHL3 transcription and destabilizes UCHL3 protein stability. Further studies showed that UCHL3 dysfunction triggered excessive GOPC ubiquitination and proteasomal destruction. Our study provided the first mechanistic evidence linking an environmental toxin (MC-LR) to ubiquitination-dependent failure of spermiogenesis, specifically through GOPC degradation. We identified disruption of the UCHL3-GOPC regulatory axis as a novel etiological pathway in MC-LR-induced male infertility, highlighting this axis as a promising therapeutic target for chemical-induced reproductive dysfunction.