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

Date Published: September 13, 2019

Publisher: Public Library of Science

Author(s): Liang Wei Wang, Zhonghao Wang, Ina Ersing, Luis Nobre, Rui Guo, Sizun Jiang, Stephen Trudeau, Bo Zhao, Michael P. Weekes, Benjamin E. Gewurz, Michael Lagunoff.


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.

Partial Text

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 B-cell 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 [2–4]. EBV causes endemic Burkitt’s lymphoma (BL), the most common pediatric lymphoma in sub-Saharan Africa [5, 6] and is strongly associated with a subset of Hodgkin’s lymphoma (HL) [1, 7]. 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].

Diverse DNA viruses subvert host lipid biosynthesis pathways to support viral replication, including Kaposi’s sarcoma-associated herpesvirus (KSHV) [79, 80], human cytomegalovirus (HCMV) [81–83], herpes simplex virus (HSV) [84, 85] and vaccinia virus [86]. Interestingly, KSHV subverts hypoxia inducible factors (HIF) to induce metabolic remodeling in B-cells [87], whereas in epithelial cells it targets glutamine and asparagine metabolic pathways, while suppressing glycolysis, to support transformed cell growth [88, 89]. Yet, comparatively less is known about how EBV remodels lymphocyte metabolic pathways to support cell transformation, growth and survival. While EBV strongly upregulates aerobic glycolysis in newly infected B-cells [25], presumably to supply building blocks for anabolic metabolism pathways, key downstream lipid biosynthesis pathways upregulated by latent EBV infection have remained to be identified.




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