Grass carp retinoid-related orphan receptor α (gcRORαa) promotes GCRV replication via LDLR-mediated lipid accumulation.

Despite the knowledge of some mechanisms by which viruses hijack host lipid metabolism to support their replication, it remains poorly understood how the nuclear receptor pathways are linked to lipid-dependent viral pathogenesis in fish. In this study, we investigated the role of nuclear receptor grass carp retinoid-related orphan receptor α (gcRORαa) in grass carp reovirus (GCRV) infection. gcRORαa enhances GCRV susceptibility in host cells and promotes formation of GCRV-infected VIBs, but knockdown helps CIK cells show anti-GCRV effects. Mechanistically, gcRORαa leads to cholesterol and triglyceride accumulation, thereby enhancing the process of lipid droplet biogenesis in infected cells. gcRORαa does these jobs by targeting the cholesterol metabolic pathway, and low-density lipoprotein receptor (LDLR) is an important downstream effector. It causes to increase LDLR transcription via promoter activation and increase LDLR protein expression, thereby facilitating uptake of cholesterol-rich low-density lipoprotein (LDL) from the external environment. By knocking down LDLR, one can stop the gcRORαa-mediated lipid build-up, LD/VIBs formation, and GCRV replication. On the other hand, silencing gcRORαa does not affect LDLR function. This indicates that gcRORαa works upstream of LDLR to fuel lipid-dependent viral replication. Through this study, a new gcRORαa-LDLR axis that links nuclear receptor signaling to lipid metabolism and GCRV pathogenesis is uncovered, thereby highlighting the importance of virus-fish host metabolic crosstalk, and providing potential therapeutic targets for antiviral intervention in aquaculture.