Abstract
Epstein-Barr virus (EBV) nuclear antigen 2 (EBNA2) plays an important role in driving immortalization of EBV-infected B cells through regulating the expression of many viral and cellular genes. We report a structural study of the tumor suppressor BS69/ZMYND11 C-terminal region, comprised of tandem coiled-coil-MYND domains (BS69CC-MYND), in complex with an EBNA2 peptide containing a PXLXP motif. The coiled-coil domain of BS69 self-associates to bring two separate MYND domains in close proximity, thereby enhancing the BS69 MYND-EBNA2 interaction. ITC analysis of BS69CC-MYND with a C-terminal fragment of EBNA2 further suggests that the BS69CC-MYND homodimer synergistically binds to the two EBNA2 PXLXP motifs that are respectively located in the conserved regions CR7 and CR8. Furthermore, we showed that EBNA2 interacts with BS69 and down-regulates its expression at both mRNA and protein levels in EBV-infected B cells. Ectopic BS69CC-MYND is recruited to viral target promoters through interactions with EBNA2, inhibits EBNA2-mediated transcription activation, and impairs proliferation of lymphoblastoid cell lines (LCLs). Substitution of critical residues in the MYND domain impairs the BS69-EBNA2 interaction and abolishes the BS69 inhibition of the EBNA2-mediated transactivation and LCL proliferation. This study identifies the BS69 C-terminal domains as an inhibitor of EBNA2, which may have important implications in development of novel therapeutic strategies against EBV infection.
Highlights
Epstein-Barr virus (EBV) is a widespread herpes virus that transforms resting B cells into permanent lymphoblastoid cell lines [1, 2]
Through in vivo transcription reporter and cell viability assays, we showed that ectopic expression of the BS69 coiled-coil-MYND domains leads to inhibition of the EpsteinBarr virus nuclear antigen 2 (EBNA2)-mediated transcriptional activation in the EBNA2transfected BJAB B lymphoma cell line [26], and decreased viability of lymphoblastoid cell lines (LCLs)
A previous study suggested that the interaction between BS69 and EBNA2 is mediated by the MYND domain of BS69 and the PXLXP motif from EBNA2 [22]
Summary
Epstein-Barr virus (EBV) is a widespread herpes virus that transforms resting B cells into permanent lymphoblastoid cell lines [1, 2] Under some circumstances, this may further lead to several malignancies, including Burkitt’s lymphoma, Hodgkin lymphoma and nasopharyngeal carcinoma [3]. One of the key EBV proteins that drive immortalization of B cells is EpsteinBarr virus nuclear antigen 2 (EBNA2) It is, together with another EBV protein, EBNA-LP, the first protein to be expressed upon infection [4, 5]. EBNA2 plays a critical role in controlling the expression of many viral and cellular genes [7] It recruits a variety of cellular proteins, including histone acetyltransferases (e.g. P300) [8] and basal transcription factors [9,10,11], to regulate chromatin structure and gene expression. Several other domains, including CR7, are important for EBNA2-LP coactivation [17, 18]
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