Abstract
SummaryEpstein-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 tandem-mass-tag-based proteomics at rest and at nine time points after infection; >8,000 host and 29 viral proteins were quantified, revealing mitochondrial remodeling and induction of one-carbon (1C) metabolism. EBV-encoded EBNA2 and its target MYC were required for upregulation of the central mitochondrial 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.
Highlights
Epstein-Barr virus (EBV) is a gamma-herpes virus that successfully colonizes the B cell compartment of 95% of adults worldwide and was the first identified human tumor virus
EBV is the etiological agent of infectious mononucleosis (IM) and is associated with 1% of all human cancers worldwide, including multiple B cell malignancies (Longnecker et al, 2013) such as endemic Burkitt lymphoma (BL), Hodgkin lymphoma (HL), diffuse large B cell lymphoma (DLBCL) of the elderly, and primary central nervous system lymphoma (Shannon-Lowe et al, 2017)
We found that EBV remodels B cell mitochondria and that mitochondrial one-carbon (1C) metabolism was one of the most highly induced pathways. 1C plays key roles in supporting rapid cell growth in embryonic development (Christensen and Mackenzie, 2008; Patel et al, 2005; Di Pietro et al, 2002; Patel et al, 2003), cancer (Nilsson et al, 2014), and T cell activation (Ron-Harel et al, 2016) but has not previously been studied in the context of viral oncogenesis or in primary human B cell activation
Summary
Epstein-Barr virus (EBV) is a gamma-herpes virus that successfully colonizes the B cell compartment of 95% of adults worldwide and was the first identified human tumor virus. Epstein-Barr virus (EBV) is a herpes family virus, which is commonly associated with infectious mononucleosis (‘‘mono’’ or kissing disease) and a rare number of blood cancers such as B cell lymphomas. Researchers at Cambridge University and Harvard Medical School investigated a neglected aspect of EBV infection: how EBV remodels B cell pathways to facilitate nutrient acquisition and cellular proliferation. They show that EBV infection highjacks the B cell mitochondria and the ‘‘1C folate metabolism’’ pathway, normally used in embryonic development, to provide the complex cellular building blocks and antioxidant support needed for cancer cell growth. The work provides an attractive rationale for developing novel folatedependent mitochondrial 1C metabolic inhibitors for the treatment of B lymphomas
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