Abstract
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 multiple lymphomas. Yet, knowledge of how EBV subverts host biosynthetic pathways to transform resting lymphocytes into activated lymphoblasts remains incomplete. Using a temporal proteomic dataset of EBV primary human B-cell infection, we identified that cholesterol and fatty acid biosynthetic pathways were amongst the most highly EBV induced. Epstein-Barr nuclear antigen 2 (EBNA2), sterol response element binding protein (SREBP) and MYC each had important roles in cholesterol and fatty acid pathway induction. Unexpectedly, HMG-CoA reductase inhibitor chemical epistasis experiments revealed that mevalonate pathway production of geranylgeranyl pyrophosphate (GGPP), rather than cholesterol, was necessary for EBV-driven B-cell outgrowth, perhaps because EBV upregulated the low-density lipoprotein receptor in newly infected cells for cholesterol uptake. Chemical and CRISPR genetic analyses highlighted downstream GGPP roles in EBV-infected cell small G protein Rab activation. Rab13 was highly EBV-induced in an EBNA3-dependent manner and served as a chaperone critical for latent membrane protein (LMP) 1 and 2A trafficking and target gene activation in newly infected and in lymphoblastoid B-cells. Collectively, these studies identify highlight multiple potential therapeutic targets for prevention of EBV-transformed B-cell growth and survival.
Highlights
The gamma-herpes virus Epstein-Barr virus (EBV) causes infectious mononucleosis (IM) and is associated with multiple B-cell and epithelial malignancies [1]
Upon infection of small, resting B-lymphocytes, EBV establishes a state of viral
Flow cytometry (FACS) analysis identified that newly EBV-infected primary B-cells reach a maximum size at 4 days post-infection (DPI) (Figs 1A and S1), consistent with a recent publication [35]
Summary
The gamma-herpes virus Epstein-Barr virus (EBV) causes infectious mononucleosis (IM) and is associated with multiple B-cell and epithelial malignancies [1]. EBV is a major source of Bcell lymphoproliferative disease in immunosuppressed hosts, including following organ transplantation, with human immunodeficiency virus co-infection, with immunosenescence of aging or in the setting of primary immunodeficiency [2,3,4]. While much has been learned about viral factors necessary for oncogenic transformation, knowledge remains incomplete of how EBV manipulates host metabolic pathways, a hallmark of cancer [8]. EBV translocates across the tonsillar epithelial barrier to reach the Bcell compartment, which is the reservoir for lifelong infection. Whereas epithelial cell infection typically results in production of infectious virions by the viral lytic cycle, EBV establishes latency in newly infected B-cells. In the course of IM, considerable numbers of latentlyinfected B-cells can be detected in peripheral blood [9], innate and adaptive immune responses subsequently limit the outgrowth of cells that express viral transforming proteins [10, 11]
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