ACADM inhibits AMPK activation to modulate PEDV-induced lipophagy and β-oxidation for impairing viral replication

• Published in: The Journal of biological chemistry 2024-08, Vol.300 (8), p.107549, Article 107549
• Main Authors: Wang, Quanqiong, Zhang, Qi, Shi, Xiaojie, Yang, Naling, Zhang, Yanxia, Li, Shifan, Zhao, Yina, Zhang, Shuxia, Xu, Xingang
• Format: Article
• Language: English
• Subjects: ACADM; Acyl-CoA Dehydrogenase - genetics; Acyl-CoA Dehydrogenase - metabolism; AMP-Activated Protein Kinases - metabolism; AMPK; Animals; Chlorocebus aethiops; Coronavirus Infections - metabolism; Coronavirus Infections - virology; Enzyme Activation; Fatty Acids - metabolism; HEK293 Cells; Humans; Lipid Metabolism; lipophagy; Oxidation-Reduction; PEDV; Porcine epidemic diarrhea virus - physiology; Swine; Vero Cells; Viral Nonstructural Proteins - genetics; Viral Nonstructural Proteins - metabolism; Virus Replication; β-oxidation
• ISSN: 0021-9258; 1083-351X; 1083-351X
• DOI: 10.1016/j.jbc.2024.107549

Porcine epidemic diarrhea virus (PEDV) belongs to the Alphacoronavirus genus within the Coronavirus family, causing severe watery diarrhea in piglets and resulting in significant economic losses. Medium-chain acyl-CoA dehydrogenase (ACADM) is an enzyme participating in lipid metabolism associated with metabolic diseases and pathogen infections. Nonetheless, the precise role of ACADM in regulating PEDV replication remains uncertain. In this study, we identified ACADM as the host binding partner of NSP4 via immunoprecipitation-mass spectrometry analysis. The interaction between ACADM and NSP4 was subsequently corroborated through coimmunoprecipitation and laser confocal microscopy. Following this, a notable upsurge in ACADM expression was observed during PEDV infection. ACADM overexpression effectively inhibited virus replication, whereas ACADM knockdown facilitated virus replication, suggesting ACADM has negative regulation effect on PEDV infection. Furthermore, we demonstrated fatty acid β-oxidation affected PEDV replication for the first time, inhibition of fatty acid β-oxidation reduced PEDV replication. ACADM decreased PEDV-induced β-oxidation to suppress PEDV replication. Mechanistically, ACADM reduced cellular free fatty acid levels and subsequent β-oxidation by hindering AMPK-mediated lipophagy. In summary, our results reveal that ACADM plays a negative regulatory role in PEDV replication by regulating lipid metabolism. The present study introduces a novel approach for the prevention and control of PEDV infection.