Epstein-Barr-Virus-Induced One-Carbon Metabolism Drives B Cell Transformation

被引：135

作者：

Wang, Liang Wei ^{[1
,2
,10
]}

Shen, Hongying ^{[3
,4
,5
,6
]}

Nobre, Luis ^{[7
]}

Ersing, Ina ^{[2
]}

Paulo, Joao A. ^{[8
]}

Trudeau, Stephen ^{[2
]}

Wang, Zhonghao ^{[2
,9
]}

Smith, Nicholas A. ^{[2
]}

Ma, Yijie ^{[2
]}

Reinstadler, Bryn ^{[3
,4
,5
,6
]}

Nomburg, Jason ^{[1
,2
]}

Sommermann, Thomas ^{[2
]}

Cahir-McFarland, Ellen ^{[2
]}

Gygi, Steven P. ^{[8
]}

Mootha, Vamsi K. ^{[3
,4
,5
,6
]}

Weekes, Michael P. ^{[7
]}

Gewurz, Benjamin E. ^{[1
,2
,6
,10
]}

机构：

[1] Harvard Med Sch, Div Med Sci, Grad Program Virol, 77 Ave Louis Pasteur, Boston, MA 02115 USA

[2] Brigham & Womens Hosp, Dept Med, Div Infect Dis, 181 Longwood Ave, Boston, MA 02115 USA

[3] Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA

[4] Massachusetts Gen Hosp, Howard Hughes Med Inst, Boston, MA 02114 USA

[5] Harvard Med Sch, Dept Syst Biol, Boston, MA 02115 USA

[6] Broad Inst Harvard & MIT, Cambridge, MA 02142 USA

[7] Univ Cambridge, Cambridge Inst Med Res, Hills Rd, Cambridge CB2 0XY, England

[8] Harvard Med Sch, Dept Cell Biol, Boston, MA 02115 USA

[9] Sichuan Univ, West China Hosp, Dept Lab Med, Chengdu 610041, Sichuan, Peoples R China

[10] Harvard Med Sch, Dept Microbiol, Boston, MA 02115 USA

来源：

CELL METABOLISM | 2019年 / 30卷 / 03期

关键词：

DECOY SEARCH STRATEGY; METHYLENETETRAHYDROFOLATE DEHYDROGENASE; NUCLEAR ANTIGEN-2; METHENYLTETRAHYDROFOLATE CYCLOHYDROLASE; SERINE SYNTHESIS; EXPRESSION; GENE; INFECTION; REVEALS; GENOME;

D O I：

10.1016/j.cmet.2019.06.003

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

Epstein-Barr virus (EBV) causes Burkitt, Hodgkin, and post-transplant B cell lymphomas. How EBV remodels metabolic pathways to support rapid B cell outgrowth remains largely unknown. To gain insights, primary human B cells were profiled by tandemmass-tag-based proteomics at rest and at nine time points after infection; >8,000 host and 29 viral proteins were quantified, revealing mitochondria! remodeling and induction of one-carbon (1C) metabolism. EBV-encoded EBNA2 and its target MYC were required for upregulation of the central mitochondria! 1C enzyme MTHFD2, which played key roles in EBV-driven B cell growth and survival. MTHFD2 was critical for maintaining elevated NADPH levels in infected cells, and oxidation of mitochondrial NADPH diminished B cell proliferation. Tracing studies underscored contributions of 1C to nucleotide synthesis, NADPH production, and redox defense. EBV upregulated import and synthesis of serine to augment 1C flux. Our results highlight EBV-induced 1C as a potential therapeutic target and provide a new paradigm for viral onco-metabolism.

引用

页码：539 / +

页数：28

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