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.

PD-1 and PD-L1 Expression on Circulating Lymphocytes as a Marker of Epstein-Barr Virus Reactivation-Associated Proliferative Glomerulonephritis

“…It is worth noticing, that EBV is enumerated among human viruses with a proven role in oncogenesis, and the development of autoimmune disorders, as well as immunosuppression [40][41][42][43]. The life cycle of EBV is particularly complex and the virus undergoes the latency phase during which it expresses several genes impacting oncogenesis [44][45][46][47]. Recent studies have shown that EBV DNA is present in large quantities in patients with autoimmune diseases of several etiologies [48,49].…”

Glutaminolysis dynamics during astrocytoma progression correlates with tumor aggressiveness

“…GLSiso2 is activated by inorganic phosphate [ 39 ] and it is also under c– Myc oncogene influence, through a mechanism involving miRNA [ 43 , 44 ]. The c-Myc can also upregulate the GLS isoforms KGA and GAC at protein levels increasing the levels of intracellular glutamate in Epstein-Barr virus-infected cells [ 68 ]. Oscillation of GLSiso2 expression has been associated with oxygen concentration, with an increase in hypoxic conditions [ 39 ].…”

Metabolic Reprogramming and Immune Evasion in Nasopharyngeal Carcinoma

“…Moreover, the expression of GLS1-encoded glutaminase K (KGA) and glutaminase C (GAC) is increased in EBV-infected NPC cells. In addition, the expression of glutamate dehydrogenase 1 (GLUD1) and glutamate dehydrogenase 2 (GLUD2) is also upregulated in NPC cells, and they catalyse the conversion of glutamate to α–ketoglutarate ( 81 ). Mounting evidence suggests that the protein levels of KGA and GAC are controlled by c-MYC expression, promoting glutamine catabolism ( 82 ).…”