Epstein-Barr virus subverts mevalonate and fatty acid pathways to promote infected B-cell proliferation and survival.

摘要: Epstein-Barr virus (EBV) causes infectious mononucleosis and is associated with multiple human malignancies. EBV drives B-cell proliferation, which contributes to the pathogenesis of lymphomas. Yet, knowledge how subverts host biosynthetic pathways transform resting lymphocytes into activated lymphoblasts remains incomplete. Using a temporal proteomic dataset primary infection, we identified that cholesterol fatty acid were amongst most highly induced. nuclear antigen 2 (EBNA2), sterol response element binding protein (SREBP) MYC each had important roles in pathway induction. Unexpectedly, HMG-CoA reductase inhibitor chemical epistasis experiments revealed mevalonate production geranylgeranyl pyrophosphate (GGPP), rather than cholesterol, was necessary for EBV-driven outgrowth, perhaps because upregulated low-density lipoprotein receptor newly infected cells uptake. Chemical CRISPR genetic analyses highlighted downstream GGPP EBV-infected cell small G Rab activation. Rab13 EBV-induced an EBNA3-dependent manner served as chaperone critical latent membrane (LMP) 1 2A trafficking target gene activation lymphoblastoid B-cells. Collectively, these studies identify highlight potential therapeutic targets prevention EBV-transformed growth survival.