SIRT2 deacylase modulators control B cell metabolic reprogramming in EBV infection and mitogenic activation

Sirtuin-2 (SIRT2) is a cellular deacylase, regulating cell cycle progression and metabolic homeostasis. Recently, SIRT2 has emerged as a target with both anticancer and antiviral potential. However, the role and targetability of SIRT2 in viral-driven cancers remains unexplored. Epstein-Barr virus (EBV) is a ubiquitous herpesvirus with oncogenic potential that establishes latency in B lymphocytes and is typically controlled by a robust T cell immune response. In settings that compromise this response, such as immune suppression following transplant, EBV can cause B cell lymphomas. With broad immunosuppression and varying response rates limiting the effectiveness of existing lymphoma therapeutics, new strategies are necessary. SIRT2 modulation significantly alters gene expression and metabolism of EBV-infected B cells. Treatment with SIRT2 modulators drives hyperacetylation of targets involved in lipid metabolism, central carbon metabolism, and oxidative phosphorylation. EBV-positive and EBV-negative B cell lymphomas rely on glycolysis to avoid cell death after SIRT2 modulation, revealing a metabolic vulnerability that can be harnessed to kill lymphoma cells. Overall, we have identified how SIRT2 could be implicated as a novel target of therapeutic potential for B cell lymphomas, while also defining fundamental roles for extranuclear lysine acetylation in regulating B cell proliferation and metabolism.