CDK6-dependent metabolic reprogramming in KSHV pathogenesis

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.