Increased association between Epstein-Barr virus EBNA2 from type 2 strains and the transcriptional repressor BS69 restricts EBNA2 activity
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Uncorrected Proof
Author(s)
Type
Journal Article
Abstract
Natural variation separates Epstein-Barr virus (EBV) into type 1 and type 2 strains. Type 2 EBV is less transforming in vitro due to sequence differences in the EBV transcription factor EBNA2. This correlates with reduced activation of the EBV oncogene LMP1 and some cell genes. Transcriptional activation by type 1 EBNA2 can be suppressed through the binding of two PXLXP motifs in its transactivation domain (TAD) to the dimeric coiled-coil MYND domain (CC-MYND) of the BS69 repressor protein (ZMYND11). We identified a third conserved PXLXP motif in type 2 EBNA2. We found that type 2 EBNA2 peptides containing this motif bound BS69CC-MYND efficiently and that the type 2 EBNA2TAD bound an additional BS69CC-MYND molecule. Full-length type 2 EBNA2 also bound BS69 more efficiently in pull-down assays. Molecular weight analysis and low-resolution structures obtained using small-angle X-ray scattering showed that three BS69CC-MYND dimers bound two molecules of type 2 EBNA2TAD, in line with the dimeric state of full-length EBNA2 in vivo. Importantly, mutation of the third BS69 binding motif in type 2 EBNA2 improved B-cell growth maintenance and the transcriptional activation of the LMP1 and CXCR7 genes. Our data indicate that increased association with BS69 restricts the function of type 2 EBNA2 as a transcriptional activator and driver of B cell growth and may contribute to reduced B-cell transformation by type 2 EBV.
Date Issued
2019-07-08
Date Acceptance
2019-06-09
Citation
PLoS Pathogens, 2019, 15 (7)
ISSN
1553-7366
Publisher
Public Library of Science (PLoS)
Journal / Book Title
PLoS Pathogens
Volume
15
Issue
7
Copyright Statement
© 2019 Ponnusamy et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Sponsor
Medical Research Council
Identifier
https://www.ncbi.nlm.nih.gov/pubmed/31283782
PII: PPATHOGENS-D-18-02105
Grant Number
MR/N010388/1
Subjects
Virology
0605 Microbiology
1107 Immunology
1108 Medical Microbiology
Publication Status
Published online
Coverage Spatial
United States
Article Number
e1007458
Date Publish Online
2019-07-08