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

English version

Autoři: Liang Wei Wang ^aff001; Zhonghao Wang ^aff002; Ina Ersing ^aff002; Luis Nobre ^aff006; Rui Guo ^aff002; Sizun Jiang ^aff002; Stephen Trudeau ^aff002; Bo Zhao ^aff002; Michael P. Weekes ^aff006; Benjamin E. Gewurz ^aff001
Působiště autorů: Graduate Program in Virology, Division of Medical Sciences, Harvard Medical School, Boston, Massachusetts, United States of America ^aff001; Division of Infectious Diseases, Department of Medicine, Brigham and Women’s Hospital, Boston, Massachusetts, United States of America ^aff002; Department of Microbiology, Harvard Medical School, Boston, Massachusetts, United States of America ^aff003; Broad Institute of Harvard and MIT, Cambridge, Massachusetts, United States of America ^aff004; Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan, People’s Republic of China ^aff005; Cambridge Institute for Medical Research, University of Cambridge, Cambridge, United Kingdom ^aff006
Vyšlo v časopise: Epstein-Barr virus subverts mevalonate and fatty acid pathways to promote infected B-cell proliferation and survival. PLoS Pathog 15(9): e32767. doi:10.1371/journal.ppat.1008030
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1008030

Souhrn

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.

Klíčová slova:

Biology and life sciences – Cell biology – Genetics – Gene expression – Biochemistry – Organisms – Research and analysis methods – Proteins – DNA-binding proteins – Molecular biology – Gene regulation – Molecular biology techniques – Cellular types – Animal cells – Medicine and health sciences – Microbiology – Medical microbiology – Microbial pathogens – Pathology and laboratory medicine – Pathogens – Transcription factors – Regulatory proteins – Viral pathogens – Viruses – Immunology – Lipids – Fatty acids – Biosynthesis – Blood cells – White blood cells – Immune cells – Antibody-producing cells – B cells – Cholesterol – DNA viruses – Herpesviruses – Epstein-Barr virus – Molecular probe techniques – Immunoblot analysis

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