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.
Highlights
Epstein–Barr virus (EBV) or human herpesvirus 4 (HHV-4) is an oncogenic virus that infects and establishes latency in more than 90% of the world’s human population
While the positive control detected a single band at 66 kDa, all the lymphoma cells including BJAB detected GLS1 as two distinct bands: one upper band at 66 kDa, which is same as the positive control, and one lower band at 58 kDa (Figure 1a), probably representing the KGA and GAC isoforms of GLS1
As we observed a significant increase in KGA and GAC, glutamate dehydrogenase 1 (GLUD1) and GLUD2 expression, and the production of alpha-ketoglutarate in EBV-infected cells, we hypothesized that enhanced glutaminolysis through KGA and GAC may be an important component in enhancing mitochondrial metabolism and supporting cellular processes such as cell proliferation
Summary
Epstein–Barr virus (EBV) or human herpesvirus 4 (HHV-4) is an oncogenic virus that infects and establishes latency in more than 90% of the world’s human population. EBV is associated with a variety of B-cell lymphomas, such as Burkitt’s lymphoma, Hodgkin’s lymphoma, and post-transplantation lymphoproliferative disorders, and two epithelial cancers, nasopharyngeal carcinoma and gastric carcinoma [1,2,3]. Burkitt’s lymphoma is associated with the expression of type I latency genes, EBV-nuclear antigen 1 (EBNA1) and EBV-encoded RNAs (EBERs). Hodgkin’s lymphoma and nasopharyngeal carcinoma are characterized by the expression of type II latency genes, EBNA1, latent membrane protein 1 (LMP1), LMP2A, LMP2B, and EBERs. In post-transplantation lymphoproliferative diseases and in vitro immortalized lymphoblastoid cell lines (LCLs), EBV has the most composite expression profile, latency III, which involves the expression of five EBNAs (EBNA1, 2, 3A, 3B, 3C), two LMPs (LMP1, LMP2A), and two EBERs [4,5,6]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
