Upregulation of GLS1 isoforms KGA and GAC facilitates mitochondrial metabolism and cell proliferation in Epstein-Barr virus infected cells

Abstract

Epstein-Barr virus or human herpesvirus 4 (EBV/HHV-4) is a ubiquitous human virus associated with a wide range of malignant neoplasms. The interaction between EBV latent proteins and host cellular molecules often leads to oncogenic transformation, promoting the development of EBV-associated cancers. The present study identifies a functional role of GLS1 isoforms KGA and GAC in regulating mitochondrial energy metabolism to promote EBV-infected cell proliferation. Our data demonstrate increased expression of GLS1 isoforms KGA and GAC with mitochondrial localization in latently EBV-infected cells and de novo EBV-infected PBMCs. c-Myc upregulates KGA and GAC protein levels, which in turn elevate the levels of intracellular glutamate. Further analysis demonstrated upregulated expression of mitochondrial GLUD1 and GLUD2, with a subsequent increase in alpha-ketoglutarate levels that may mark the activation of glutaminolysis. Cell proliferation and viability of latently EBV-infected cells were notably inhibited by KGA/GAC, as well as GLUD1 inhibitors. Taken together, our results suggest that c-Myc-dependent regulation of KGA and GAC enhances mitochondrial functions to support the rapid proliferation of the EBV-infected cells, and these metabolic processes could be therapeutically exploited by targeting KGA/GAC and GLUD1 to prevent EBV-associated cancers.