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. Here, we report that SIRT2-selective compounds block EBV-mediated B cell transformation and EBV or mitogen-driven B cell division in vitro. SIRT2 modulation significantly alters gene expression and metabolism of EBV-infected B cells, reducing mitochondrial respiration, driving mitochondrial swelling, and inducing nutrient stress and autophagy. 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 target of therapeutic potential for B cell lymphomas, while also defining fundamental roles for extranuclear lysine acetylation in regulating B cell proliferation and metabolism.