METTL16 and S-adenosylmethionine cycle in KSHV infection

Programmed metabolic pathways provide the building blocks, energy and signaling molecules required for viral infection. Kaposi’s sarcoma-associated herpesvirus (KSHV) is the causal agent of Kaposi’s sarcoma (KS) and several other malignancies. While KSHV lytic infection is responsible for viral spread and KS initiation, latent infection is essential for viral persistence and long-term KS development. We have previously found that KSHV reprograms metabolic pathways and N6-methyladenosine (m6A) epitranscriptome during infection. Significantly, KSHV reprogramed m6A epitranscriptome rewires multiple metabolic pathways during both latent and lytic infections. In particular, KSHV LANA and RTA interact with and alter the function of m6A writer protein METTL16 to reprogram the methionine/S-adenosylmethionine (SAM) cycle, maximizing both viral latent and lytic infections, respectively. Genetic or chemical inhibition of METLL16 or its key target gene MAT2A disrupts KSHV latency and promotes viral lytic infection as a result of inhibition of the SAM cycle. Our Central Hypothesis is that KSHV manipulates cellular methionine/SAM cycle to maximize both latent and lytic infections by hijacking METTL16 to reprogram specific m6A marks. We will identify KSHV-regulated METTL16-specific m6A marks at a single-base resolution during latent and lytic infections and determine their mechanisms of regulation of the SAM cycle (Aim 1), delineate the mechanisms of regulation of KSHV latent and lytic infections by the SAM cycle (Aim 2), and define the mechanisms by which KSHV hijacks METTL16 to deregulate m6A epitranscriptome and the SAM cycle during latent and lytic infections (Aim 3). We have assembled a multidisciplinary team with diverse expertise in KSHV biology, KS pathology, metabolism, proteomics and computational biology for addressing the complex issues in this project. This project is highly innovative as it will converge the emerging advancements in epitranscriptomics and metabolism fields, and define their roles in KSHV infection. The project is highly significant as the outcomes will reveal novel mechanisms regulating KSHV latent and lytic infections, which will lead to the discovery of novel therapeutic targets for KSHV-induced cancers.