Epstein-Barr virus ensures B cell survival by uniquely modulating apoptosis at early and late times after infection
- Duke University School of Medicine, United States
- Imperial College London, United Kingdom
- Harvard Medical School, United States
- University of Wisconsin School of Medicine and Public Health, United States
- Duke University, United States
Abstract
Latent Epstein-Barr virus (EBV) infection is causally linked to several human cancers. EBV expresses viral oncogenes that promote cell growth and inhibit the apoptotic response to uncontrolled proliferation. The EBV oncoprotein LMP1 constitutively activates NFB and is critical for survival of EBV-immortalized B cells. However, during early infection EBV induces rapid B cell proliferation with low levels of LMP1 and little apoptosis. Therefore, we sought to define the mechanism of survival in the absence of LMP1/NFB early after infection. We used BH3 profiling to query mitochondrial regulation of apoptosis and defined a transition from uninfected B cells (BCL-2) to early-infected (MCL-1/BCL-2) and immortalized cells (BFL-1). This dynamic change in B cell survival mechanisms is unique to virus-infected cells and relies on regulation of MCL-1 mitochondrial localization and BFL-1 transcription by the viral EBNA3A protein. This study defines a new role for EBNA3A in the suppression of apoptosis with implications for EBV lymphomagenesis.
Data availability
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EBNA2 ChIP-SeqPublicly available at the NCBI Gene Expression Omnibus (accession no: GSE29498).
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The NF-kB genomic landscape in lymphoblastoid B-cellsPublicly available at the NCBI Gene Expression Omnibus (accession no: GSE55105).
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EBNA3C ChIP-SeqPublicly available at the NCBI Gene Expression Omnibus (accession no: GSE52632).
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EBNA3A ChIP-SeqPublicly available at the NCBI Gene Expression Omnibus (accession no: GSE59181).
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Histone modifications in LCLs (ENCODE)Publicly available at the NCBI Gene Expression Omnibus (accession no: GSE29611).
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TF binding sites in LCLs (ENCODE)Publicly available at the NCBI Gene Expression Omnibus (accession no: GSE31477).
Article and author information
Author details
Funding
National Cancer Institute (R01-CA140337)
- Micah A Luftig
American Cancer Society (RSG-13-228-01-MPC)
- Micah A Luftig
Wellcome (099273/Z/12/Z)
- Quentin Bazot
- Martin J Allday
National Institute for Dental and Cranofacial Research (R01-DE025994)
- Joanne Dai
- Micah A Luftig
National Institute for Allergy and Infectious Diseases (5P30-AI064518)
- Micah A Luftig
National Cancer Institute (F31-CA180451)
- Alexander M Price
National Institute for Dental and Cranofacial Research (R01-DE023939)
- Eric C Johannsen
National Institute for Allergy and Infectious Diseases (T32-AI078985)
- Reza Djavadian
National Cancer Institute (R01-CA129974)
- Anthony Letai
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Stephen P Goff, Howard Hughes Medical Institute, Columbia University, United States
Version history
- Received: October 19, 2016
- Accepted: April 19, 2017
- Accepted Manuscript published: April 20, 2017 (version 1)
- Version of Record published: May 10, 2017 (version 2)
Copyright
© 2017, Price et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Epstein-Barr virus ensures B cell survival by uniquely modulating apoptosis at early and late times after infection
eLife 6:e22509.
https://doi.org/10.7554/eLife.22509
Further reading
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- Cancer Biology
- Genetics and Genomics
Enhancers are critical for regulating tissue-specific gene expression, and genetic variants within enhancer regions have been suggested to contribute to various cancer-related processes, including therapeutic resistance. However, the precise mechanisms remain elusive. Using a well-defined drug-gene pair, we identified an enhancer region for dihydropyrimidine dehydrogenase (DPD, DPYD gene) expression that is relevant to the metabolism of the anti-cancer drug 5-fluorouracil (5-FU). Using reporter systems, CRISPR genome-edited cell models, and human liver specimens, we demonstrated in vitro and vivo that genotype status for the common germline variant (rs4294451; 27% global minor allele frequency) located within this novel enhancer controls DPYD transcription and alters resistance to 5-FU. The variant genotype increases recruitment of the transcription factor CEBPB to the enhancer and alters the level of direct interactions between the enhancer and DPYD promoter. Our data provide insight into the regulatory mechanisms controlling sensitivity and resistance to 5-FU.
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- Cancer Biology
- Epidemiology and Global Health
Background:
Age is the most important risk factor for cancer, but aging rates are heterogeneous across individuals. We explored a new measure of aging-Phenotypic Age (PhenoAge)-in the risk prediction of site-specific and overall cancer.
Methods:
Using Cox regression models, we examined the association of Phenotypic Age Acceleration (PhenoAgeAccel) with cancer incidence by genetic risk group among 374,463 participants from the UK Biobank. We generated PhenoAge using chronological age and nine biomarkers, PhenoAgeAccel after subtracting the effect of chronological age by regression residual, and an incidence-weighted overall cancer polygenic risk score (CPRS) based on 20 cancer site-specific polygenic risk scores (PRSs).
Results:
Compared with biologically younger participants, those older had a significantly higher risk of overall cancer, with hazard ratios (HRs) of 1.22 (95% confidence interval, 1.18–1.27) in men, and 1.26 (1.22–1.31) in women, respectively. A joint effect of genetic risk and PhenoAgeAccel was observed on overall cancer risk, with HRs of 2.29 (2.10–2.51) for men and 1.94 (1.78–2.11) for women with high genetic risk and older PhenoAge compared with those with low genetic risk and younger PhenoAge. PhenoAgeAccel was negatively associated with the number of healthy lifestyle factors (Beta = –1.01 in men, p<0.001; Beta = –0.98 in women, p<0.001).
Conclusions:
Within and across genetic risk groups, older PhenoAge was consistently related to an increased risk of incident cancer with adjustment for chronological age and the aging process could be retarded by adherence to a healthy lifestyle.
Funding:
This work was supported by the National Natural Science Foundation of China (82230110, 82125033, 82388102 to GJ; 82273714 to MZ); and the Excellent Youth Foundation of Jiangsu Province (BK20220100 to MZ).
