# CDK6-dependent metabolic reprogramming in KSHV pathogenesis

> **NIH NIH R01** · CLEVELAND CLINIC LERNER COM-CWRU · 2024 · $466,273

## Abstract

Project Summary
Metabolic reprogramming is one of the hallmarks for cancer. Emerging studies show that viral infections induce
similar metabolic rewiring for viral persistence and propagation. Human Kaposi's sarcoma-associated
herpesvirus (KSHV) causes Kaposi's sarcoma (KS) and multiple types of B cell malignancies. Oral KS is one of
the most common clinical manifestations in AIDS patient, and is associated with higher KSHV viral loads. KSHV
infection reprograms metabolic pathways, including but not limited to glycolysis, glutaminolysis, and lipogenesis.
Nevertheless, the mechanisms by which KSHV manipulates cellular metabolism remain poorly understood. Our
recent study shows that pyrimidine biosynthesis enzyme CAD has a non-canonical function to target NF-κB
transcription factor RelA for protein deamidation. Remarkably, deamidation of RelA downregulates NF-κB
responses, but drives aerobic glycolysis to promote cell proliferation. In KSHV-infected oral keratinocytes and
endothelial cells, the viral Cyclin homology, vCyclin, hijacks cellular Cyclin-dependent kinase 6 (CDK6) to
phosphorylate CAD, thereby driving pyrimidine biosynthesis and deamidation-dependent glycolysis. Besides
CAD, our preliminary data suggest that vCyclin-CDK6 complex phosphorylates fatty acid synthesis enzymes to
reprogram de novo fatty acid synthesis. These findings support our overarching hypothesis that KSHV exploits
host CDK6 for metabolic reprogramming to facilitate viral replication and tumorigenesis. In the proposed study,
we will determine the mechanisms by which KSHV vCyclin-CDK6-mediated phosphorylations regulate metabolic
enzymes (Aim 1), delineate KSHV-driven reprogramming of metabolic pathways by vCyclin-CDK6 (Aim 2), and
determine the physiological relevance of CDK6-mediated metabolic reprogramming in KSHV pathogenesis (Aim
3). Overall, the proposed study will identify unprecedented mechanisms underlying viral manipulations of
glycolysis, nucleotide synthesis, and fatty acid synthesis. Our research will also uncover CDK6-associated
metabolic vulnerabilities of KSHV-infected cells which will establish the foundation for the development of novel
therapeutics against KSHV-associated malignancies.

## Key facts

- **NIH application ID:** 11006503
- **Project number:** 1R01DE033632-01A1
- **Recipient organization:** CLEVELAND CLINIC LERNER COM-CWRU
- **Principal Investigator:** Jun Zhao
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $466,273
- **Award type:** 1
- **Project period:** 2024-09-01 → 2029-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11006503

## Citation

> US National Institutes of Health, RePORTER application 11006503, CDK6-dependent metabolic reprogramming in KSHV pathogenesis (1R01DE033632-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/11006503. Licensed CC0.

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