KSHV vIRF3–PKM2 interaction induces SMAD5 acetylation, promoting Kaposi’s sarcoma progression

Abstract Kaposi’s sarcoma (KS), induced by Kaposi’s sarcoma-associated herpesvirus (KSHV), is a multicentric tumor of lymphatic endothelial origin. However, the fundamental molecular mechanisms underlying the KS progression remain poorly understood. Here we found that interaction between KSHV vIRF3 and PKM2 controls the metabolic switch of lymphatic endothelial cells (LECs), inducing disseminated visceral KS in xenograft models of KSHV-infected LECs. Mechanistically, vIRF3–PKM2 interaction elevates intracellular acetyl coenzyme A (acetyl-CoA) level by augmenting the PKM2 enzymatic activity, leading to SMAD5 acetylation, which contributes to the endothelia-to-mesenchymal transition of LECs. Notably, a vIRF3-derived short peptide acts as a potent and selective PKM2 antagonist, effectively regressing KS progression. Collectively, these results suggest that vIRF3 plays a pivotal role in KS malignancy by linking acetyl-CoA metabolic reprogramming to cancer progression.