Increased association between Epstein-Barr virus EBNA2 from type 2 strains and the transcriptional repressor BS69 restricts EBNA2 activity
Increased association between Epstein-Barr virus EBNA2 from type 2 strains and the transcriptional repressor BS69 restricts EBNA2 activity
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DOI：
10.1371/journal.ppat.1007458
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发表时间：
2019-07
期刊：
影响因子：
6.7
通讯作者：
R. Ponnusamy;Ritika Khatri;Paulo B. Correia;C. Wood;E. Mancini;Paul J. Farrell;M. West
中科院分区：
文献类型：
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作者：
R. Ponnusamy;Ritika Khatri;Paulo B. Correia;C. Wood;E. Mancini;Paul J. Farrell;M. West
自然变异将EB病毒（EBV）分为1型和2型毒株。由于EBV转录因子EBNA 2的序列差异，2型EBV在体外转化较少。这与EBV癌基因LMP 1和一些细胞基因的激活减少有关。1型EBNA 2的转录激活可以通过其反式激活结构域（ZMND）中的两个PXLXP基序与BS 69阻遏蛋白（ZMYND 11）的二聚卷曲螺旋MYND结构域（CC-MYND）的结合来抑制。我们在2型EBNA 2中鉴定了第三个保守的PXLXP基序。我们发现，含有该基序的2型EBNA 2肽有效地结合BS 69 CC-MYND，并且2型EBNA 2肽结合另外的BS 69 CC-MYND分子。全长2型EBNA 2在下拉测定中也更有效地结合BS 69。使用小角X射线散射获得的分子量分析和低分辨率结构表明，三个BS 69 CC-MYND二聚体结合2型EBNA 2 β的两个分子，与体内全长EBNA 2的二聚体状态一致。重要的是，2型EBNA 2中第三个BS 69结合基序的突变改善了B细胞生长维持和LMP 1和CXCR 7基因的转录激活。我们的数据表明，与BS 69的关联增加限制了2型EBNA 2作为转录激活因子和B细胞生长驱动因子的功能，并可能有助于减少2型EBV对B细胞的转化。
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.