Oncolytic avian reovirus A-modulated fatty acid metabolism through the PSMB6/Akt/SREBP1/acetyl-CoA carboxylase pathway to increase energy production for virus replication

We have demonstrated previously that the sigma A protein of avian reovirus (ARV) functions as an activator of cellular energy, which upregulates glycolysis and the TCA cycle for virus replication. To date, there is no report with respect to sigma A-modulated regulation of cellular fatty acid metabolism. This study reveals that the sigma A protein of ARV inhibits fatty acids synthesis and enhance fatty acid oxidation by upregulating PSMB6, which suppresses Akt, sterol regulatory element-binding protein 1 (SREBP1), acetyl-coA carboxylase alpha (ACC1), and acetyl-coA carboxylase beta (ACC2). SREBP1 is a transcription factor involved in fatty acid and cholesterol biosynthesis. Overexpression of SREBP1 reversed sigma A-modulated suppression of ACC1 and ACC2. In this work, a fluorescence resonance energy transfer-based genetically encoded indicator, Ateams, was used to study sigma A-modulated inhi-bition of fatty acids synthesis which enhances cellular ATP levels in Vero cells and human cancer cell lines (A549 and HeLa). By using Ateams, we demonstrated that sigma A-modulated inhibition of Akt, SREBP1, ACC1, and ACC2 leads to increased levels of ATP in mammalian and human cancer cells. Furthermore, knockdown of PSMB6 or overexpression of SREBP1 reversed sigma A-modulated increased levels of ATP in cells, indicating that PSMB6 and SREBP1 play important roles in ARV sigma A-modulated cellular fatty acid metabolism. Furthermore, we found that sigma A R155/273A mutant protein loses its ability to enter the nucleolus, which impairs its ability to regulate fatty acid metabolism and does not increase ATP formation, suggesting that nucleolus entry of sigma A is critical for regulating cellular fatty acid metabolism to generate more energy for virus replication. Collectively, this study provides novel insights into sigma A-modulated inhibition of fatty acid synthesis and enhancement of fatty acid oxidation to produce more energy for virus replication through the PSMB6/Akt/SREBP1/ACC pathway.