10.17863/CAM.43039
Wang, Liang Wei
0000-0002-0324-8744
Wang, Zhonghao
Ersing, Ina
Nobre, Luis
0000-0003-0467-8989
Guo, Rui
0000-0003-4584-1324
Jiang, Sizun
0000-0001-6149-3142
Trudeau, Stephen
Zhao, Bo
Weekes, Michael P
0000-0003-3196-5545
Gewurz, Benjamin E
Epstein-Barr virus subverts mevalonate and fatty acid pathways to promote infected B-cell proliferation and survival.
Public Library of Science (PLoS)
2019
Alkyl and Aryl Transferases
B-Lymphocytes
Cell Proliferation
Cell Survival
Cholesterol
Epstein-Barr Virus Infections
Epstein-Barr Virus Nuclear Antigens
Fatty Acids
Herpesvirus 4, Human
Host Microbial Interactions
Humans
Metabolic Networks and Pathways
Mevalonic Acid
Proto-Oncogene Proteins c-myc
Sterol Regulatory Element Binding Protein 2
Viral Proteins
rab GTP-Binding Proteins
Apollo - University of Cambridge Repository
University of Cambridge
013meh722
2019-08-19
2019-08-19
2019-09
eng
Article
https://www.repository.cam.ac.uk/handle/1810/295991
10.1371/journal.ppat.1008030
All rights reserved
open.access
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.
Wellcome Trust
108070/Z/15/Z