Role of OGDH in Atophagy-IRF3-IFN-β pathway during classical swine fever virus infection

Abstract

Classical swine fever (CSF) is a severe infectious disease caused by the classical swine fever virus (CSFV) that poses significant challenges to the swine industry. α-ketoglutarate dehydrogenase (OGDH), the first rate-limiting enzyme of the tricarboxylic acid (TCA) cycle, catalyzes α-ketoglutarate (α-KG) to succinyl-CoA, playing a crucial role in glycometabolism. Our previous studies showed that CSFV disrupts the TCA cycle, resulting in α-KG accumulation. However, the interplay between CSFV and OGDH remains unclear. In this study, we found that CSFV significantly reduces OGDH protein levels and promotes α-KG secretion through OGDH in PK-15 cells. Furthermore, we observed CSFV C protein interacts with OGDH and revealed that CSFV utilizes NDP52/NBR1 to target OGDH protein degradation in the autophagy-lysosome pathway. We also unveiled that OGDH overexpression inhibits CSFV proliferation, whereas OGDH knockdown increases CSFV proliferation. Further investigation into the mechanisms of OGDH on CSFV replication revealed that OGDH regulates the AMPK-mTOR-autophagy pathway. Additionally, using the autophagy agonist/inhibitor, rapamycin/3-MA, we observed that OGDH modulates autophagy to regulate the IRF3-IFN-β network and CSFV replication. These findings shed light on the role of OGDH in CSFV infection and host metabolism, promoting the development of innovative strategies for combating CSFV and other viral infections via targeting metabolic pathways.