Hijacking of nucleotide biosynthesis and deamidation-mediated glycolysis by an oncogenic herpesvirus
Abstract
Kaposi’s sarcoma-associated herpesvirus (KSHV) is the causative agent of Kaposi’s sarcoma (KS) and multiple types of B cell malignancies. Emerging evidence demonstrates that KSHV reprograms host-cell central carbon metabolic pathways, which contributes to viral persistence and tumorigenesis. However, the mechanisms underlying KSHV-mediated metabolic reprogramming remain poorly understood. Carbamoyl-phosphate synthetase 2, aspartate transcarbamoylase, and dihydroorotase (CAD) is a key enzyme of the de novo pyrimidine synthesis, and was recently identified to deamidate the NF-κB subunit RelA to promote aerobic glycolysis and cell proliferation. Here we report that KSHV infection exploits CAD for nucleotide synthesis and glycolysis. Mechanistically, KSHV vCyclin binds to and hijacks cyclin-dependent kinase CDK6 to phosphorylate Ser-1900 on CAD, thereby activating CAD-mediated pyrimidine synthesis and RelA-deamidation-mediated glycolytic reprogramming. Correspondingly, genetic depletion or pharmacological inhibition of CDK6 and CAD potently impeded KSHV lytic replication and thwarted tumorigenesis of primary effusion lymphoma (PEL) cells in vitro and in vivo. Altogether, our work defines a viral metabolic reprogramming mechanism underpinning KSHV oncogenesis, which may spur the development of new strategies to treat KSHV-associated malignancies and other diseases.
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© The Author(s) 2024. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
Acknowledgement
We thank Dr. Pinghui Feng (University of Southern California) for cell lines and the support in mass spectrometry analysis. We are also grateful to Dr. Jae U Jung (Cleveland Clinic), Dr. Michael Lagunoff (University of Washington), Dr. Ren Sun (University of California Los Angeles) and Dr. Young-Kwon Hong (University of Southern California) for cell lines and KSHV reagents. We also thank Cleveland Clinic Lerner Research Institute Proteomics and Metabolomics Core, as well as Florida Research and Innovation Flow Cytometry Core for services and analyses. J.Z. is supported by a grant from NIDCR (R00DE028973), startup funds from the Cleveland Clinic Florida Research and Innovation Center, and a Cleveland Clinic Global Center for Pathogen and Human Health Research Fast Track Research Award. Z.H. is supported by a grant from NIAID (R01AI173277).
Contributions
Q.W. and J.Z. designed the experiments. Q.W., L.T., T.Y.W., A.J.T., R.Z., and J.Z. performed the experiments. Q.L., S.F. and D.C. contributed to key biological resources. Q.W., L.T., T.Y.W., A.J.T., R.Z., Z.H., M.U.G. and J.Z. contributed to the interpretation of the data. J.Z. conceived the study. Q.W., M.U.G. and J.Z. wrote the manuscript, with input from all the authors.
Data Availability
The mass spectrometry proteomics data have been deposited to the ProteomeXchange80 Consortium via the PRIDE81 partner repository with the dataset identifier PXD043435. All data needed to evaluate the conclusions for the study are present in the paper. Unique expression vectors and reagents generated for this study are available upon request. Source data are provided with this paper.
Conflict of Interest
The authors declare no competing interests.
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Additional details
Identifiers
- PMCID
- PMC10873312
Funding
- National Institutes of Health
- R00DE028973
- Cleveland Clinic Florida
- National Institutes of Health
- R01AI173277