Polyglutamine-binding protein 1 protects mouse testes from heat stress

Heat exposure of the testes, a condition seen in fevers or cryptorchidism, is a well-established cause of compromised spermatogenesis and male infertility. Cells typically respond to such stresses by forming protective RNA-protein assemblies known as stress granules. While the RNA-binding factor Polyglutamine binding protein 1 (PQBP1) is known to be involved in stress responses in neurons, its specific role in the thermally sensitive testis remains unclear. Here we identify PQBP1 as a critical factor that safeguards germ cell function by orchestrating the stress granule response during testicular heat stress. Using a mouse model with a Pqbp1 Y65C mutation, we found that following heat exposure, mutant testes exhibited defective stress granule assembly. This molecular failure was accompanied by a significant reduction in sperm motility and a transcriptomic profile indicating a heightened pro-inflammatory and cellular stress state compared to wild-type controls. Our findings provide a direct mechanistic link between the cellular stress granule machinery and the physiological outcome of heat-induced sperm dysfunction. These results establish PQBP1 as a key regulator of germ cell homeostasis under thermal stress and suggest that modulating the stress granule pathway may represent a potential therapeutic avenue for mitigating certain forms of male infertility.