A viral Cyclin D homolog protein hijacks the metabolic stress sensor SESN2 to promote primary effusion lymphoma growth
Menée à l'aide de lignées cellulaires, cette étude met en évidence un mécanisme par lequel le virus de l'herpès associé au sarcome de Kaposi favorise la croissance du lymphome primitif des séreuses en stabilisant la sestrine 2 via la cycline virale D
Sestrin 2 (SESN2) is a stress-responsive protein dysregulated in cancer, yet the mechanism regulating its expression remains unclear. Here, we demonstrate that Kaposi’s sarcoma–associated herpesvirus (KSHV) exploits the stress-adaptive pathway by stabilizing SESN2 through vCyclin, which recruits the deubiquitinase OTUB1 to prevent SESN2 polyubiquitination and degradation. This stabilization promotes tumor growth by activating AMP-activated protein kinase (AMPK), a master energy homeostasis regulator hijacked by cancer to endure metabolic stress. Furthermore, vCyclin’s cytosolic localization, determined by lysine at residue 74, is required for OTUB1 recruitment and SESN2-AMPK activation. These findings reveal a viral strategy that mimics oncogenic signaling to stabilize stress sensors and identify the OTUB1–SESN2–AMPK axis as a promising therapeutic target for virus-associated and metabolically stressed cancers. 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.
Proceedings of the National Academy of Sciences , résumé, 2025