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標題: Avian reovirus σA-modulated suppression of lactate dehydrogenase and upregulation of glutaminolysis and the mTOC1/eIF4E/HIF-1α pathway to enhance glycolysis and the TCA cycle for virus replication
作者: Chi, Pei-I
Huang, Wei-Ru
Chiu, Hung-Chuan
Li, Jyun-Yi
Nielsen, Brent L
Liu, Hung-Jen
關鍵字: HIF-1α;TCA cycle;avian reovirus;glutaminolysis;glycolysis;mTOR complex 1;σA;3' Untranslated Regions;5' Untranslated Regions;Adenosine Triphosphate;Animals;Chlorocebus aethiops;Citric Acid Cycle;Eukaryotic Initiation Factor-4E;Genome, Viral;Glutamine;Glycolysis;Host-Pathogen Interactions;Hypoxia-Inducible Factor 1, alpha Subunit;Isocitrate Dehydrogenase;L-Lactate Dehydrogenase;Mechanistic Target of Rapamycin Complex 1;Orthoreovirus, Avian;RNA-Binding Proteins;Reoviridae Infections;Vero Cells;Viral Core Proteins;Virus Replication
Project: Cellular microbiology, Volume 20, Issue 12, Page(s) e12946.
Adenosine triphosphate (ATP) is an energy source for many types of viruses for facilitating virus replication. This is the first report to demonstrate that the structural protein σA of avian reovirus (ARV) functions as an activator of cellular energy. Three cellular factors, isocitrate dehydrogenase 3 subunit beta (IDH3B), lactate dehydrogenase A (LDHA), and vacuolar-type H+-ATPase (vATPase) co-immunoprecipitated with ARV σA and were identified by 2D-LC/MS/MS. ARV enhances glycolytic flux through upregulation of glycolytic enzymes. Increased ATP levels in both ARV-infected and σA-transfected cells were observed by a fluorescence resonance energy transfer-based genetically encoded indicator, Ateams. Furthermore, σA upregulates IDH3B and glutamate dehydrogenase (GDH) to promote glutaminolysis, activating HIF-1α. Both HIF-1α level and viral yield in IDH3B-depleted and glutamine-deprived cells, and inhibition of glutaminolysis was significantly reduced. The σAR155/273A mutant loses its ability to enter the nucleolus, impairing its ability to regulate glycolysis. In addition, we have identified the conserved untranslated regions (UTR) of the 5'- and 3'-termini of the ARV genome segments that are required for viral protein synthesis in an ATP-dependent manner. Deletion of either the 5'- or 3'-UTR impaired viral protein synthesis. Knockdown of σA reduced the ATP level and significantly decreased virus yield, suggesting that σA enhances ATP formation to promote virus replication. Collectively, this study provides novel insights into σA-modulated suppression of LDHA and activation of IDH3B and GDH to activate the mTORC1/eIF4E/HIF-1α pathways to upregulate glycolysis and the TCA cycle for virus replication.
DOI: 10.1111/cmi.12946
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