A viral Cyclin D homolog protein hijacks the metabolic stress sensor SESN2 to promote primary effusion lymphoma growth.

Metabolic pathways are typically dysregulated in cancer to support critical cellular processes. In response to metabolic disturbances, cancer cells preferentially manipulate stress sensors to enhance their adaptability. Sestrin 2 (SESN2), a highly conserved protein induced by various stressors, is implicated in this adaptation. Mutations and alterations of SESN2 are prevalent among cancer patients, suggesting a potential role in tumor progression. However, the functions and regulation of SESN2 in cancer, particularly in virus-induced cancer, remain largely unknown. In this study, we demonstrate that latent infection with Kaposi's sarcoma-associated herpesvirus (KSHV) stabilizes and upregulates SESN2 by inhibiting its proteasomal degradation across multiple cell lines. Notably, KSHV-encoded vCyclin, a homolog of cellular Cyclin D, directly interacts with SESN2 and promotes its stabilization by recruiting the deubiquitinase OTUB1, thereby blocking SESN2 polyubiquitination and proteasomal degradation. Moreover, vCyclin- and OTUB1-mediated stabilization of SESN2 activates AMP-activated protein kinase (AMPK), which supports the survival and growth of KSHV-driven primary effusion lymphoma cells. Importantly, the lysine at residue 74 of vCyclin is crucial for its cytosolic localization, OTUB1 recruitment, and subsequent SESN2 upregulation and AMPK activation. These findings unveil a regulatory mechanism for SESN2 involving vCyclin and OTUB1, positioning them as potential therapeutic targets for diseases associated with AMPK dysregulation.