2. Academic Validation
  3. Hijacking of nucleotide biosynthesis and deamidation-mediated glycolysis by an oncogenic herpesvirus

Hijacking of nucleotide biosynthesis and deamidation-mediated glycolysis by an oncogenic herpesvirus

  • Nat Commun. 2024 Feb 16;15(1):1442. doi: 10.1038/s41467-024-45852-5.
Quanyuan Wan 1,  Leah Tavakoli 1,  Ting-Yu Wang 2 3,  Andrew J Tucker 1,  Ruiting Zhou 1,  Qizhi Liu 2 4,  Shu Feng 2 5,  Dongwon Choi 6,  Zhiheng He 7,  Michaela U Gack 1,  Jun Zhao 8
Affiliations

Affiliations

  • 1 Florida Research and Innovation Center, Cleveland Clinic, Port St. Lucie, FL, USA.
  • 2 Section of Infection and Immunity, Herman Ostrow School of Dentistry, University of Southern California, Los Angeles, CA, USA.
  • 3 Proteome Exploration Laboratory, Beckman Institute, California Institute of Technology, Pasadena, CA, USA.
  • 4 State Laboratory of Developmental Biology of Freshwater Fish, Hunan Normal University, Changsha, Hunan, China.
  • 5 Department of Diabetes & Cancer Metabolism, Beckman Research Institute of City of Hope, Duarte, CA, USA.
  • 6 Department of Surgery, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
  • 7 Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
  • 8 Florida Research and Innovation Center, Cleveland Clinic, Port St. Lucie, FL, USA. [email protected].
PMID: 38365882 DOI: 10.1038/s41467-024-45852-5
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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