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ΔNp63α promotes Epstein-Barr virus latency in undifferentiated epithelial cells

Epstein-Barr virus (EBV) is a human herpesvirus that causes infectious mononucleosis and contributes to both B-cell and epithelial-cell malignancies. EBV-infected epithelial cell tumors, including nasopharyngeal carcinoma (NPC), are largely composed of latently infected cells, but the mechanism(s) m...

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Autores principales: Van Sciver, Nicholas, Ohashi, Makoto, Nawandar, Dhananjay M., Pauly, Nicholas P., Lee, Denis, Makielski, Kathleen R., Bristol, Jillian A., Tsao, Sai Wah, Lambert, Paul F., Johannsen, Eric C., Kenney, Shannon C.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8601603/
https://www.ncbi.nlm.nih.gov/pubmed/34748616
http://dx.doi.org/10.1371/journal.ppat.1010045
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author Van Sciver, Nicholas
Ohashi, Makoto
Nawandar, Dhananjay M.
Pauly, Nicholas P.
Lee, Denis
Makielski, Kathleen R.
Bristol, Jillian A.
Tsao, Sai Wah
Lambert, Paul F.
Johannsen, Eric C.
Kenney, Shannon C.
author_facet Van Sciver, Nicholas
Ohashi, Makoto
Nawandar, Dhananjay M.
Pauly, Nicholas P.
Lee, Denis
Makielski, Kathleen R.
Bristol, Jillian A.
Tsao, Sai Wah
Lambert, Paul F.
Johannsen, Eric C.
Kenney, Shannon C.
author_sort Van Sciver, Nicholas
collection PubMed
description Epstein-Barr virus (EBV) is a human herpesvirus that causes infectious mononucleosis and contributes to both B-cell and epithelial-cell malignancies. EBV-infected epithelial cell tumors, including nasopharyngeal carcinoma (NPC), are largely composed of latently infected cells, but the mechanism(s) maintaining viral latency are poorly understood. Expression of the EBV BZLF1 (Z) and BRLF1 (R) encoded immediate-early (IE) proteins induces lytic infection, and these IE proteins activate each other’s promoters. ΔNp63α (a p53 family member) is required for proliferation and survival of basal epithelial cells and is over-expressed in NPC tumors. Here we show that ΔNp63α promotes EBV latency by inhibiting activation of the BZLF1 IE promoter (Zp). Furthermore, we find that another p63 gene splice variant, TAp63α, which is expressed in some Burkitt and diffuse large B cell lymphomas, also represses EBV lytic reactivation. We demonstrate that ΔNp63α inhibits the Z promoter indirectly by preventing the ability of other transcription factors, including the viral IE R protein and the cellular KLF4 protein, to activate Zp. Mechanistically, we show that ΔNp63α promotes viral latency in undifferentiated epithelial cells both by enhancing expression of a known Zp repressor protein, c-myc, and by decreasing cellular p38 kinase activity. Furthermore, we find that the ability of cis-platinum chemotherapy to degrade ΔNp63α contributes to the lytic-inducing effect of this agent in EBV-infected epithelial cells. Together these findings demonstrate that the loss of ΔNp63α expression, in conjunction with enhanced expression of differentiation-dependent transcription factors such as BLIMP1 and KLF4, induces lytic EBV reactivation during normal epithelial cell differentiation. Conversely, expression of ΔNp63α in undifferentiated nasopharyngeal carcinoma cells and TAp63α in Burkitt lymphoma promotes EBV latency in these malignancies.
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spelling pubmed-86016032021-11-19 ΔNp63α promotes Epstein-Barr virus latency in undifferentiated epithelial cells Van Sciver, Nicholas Ohashi, Makoto Nawandar, Dhananjay M. Pauly, Nicholas P. Lee, Denis Makielski, Kathleen R. Bristol, Jillian A. Tsao, Sai Wah Lambert, Paul F. Johannsen, Eric C. Kenney, Shannon C. PLoS Pathog Research Article Epstein-Barr virus (EBV) is a human herpesvirus that causes infectious mononucleosis and contributes to both B-cell and epithelial-cell malignancies. EBV-infected epithelial cell tumors, including nasopharyngeal carcinoma (NPC), are largely composed of latently infected cells, but the mechanism(s) maintaining viral latency are poorly understood. Expression of the EBV BZLF1 (Z) and BRLF1 (R) encoded immediate-early (IE) proteins induces lytic infection, and these IE proteins activate each other’s promoters. ΔNp63α (a p53 family member) is required for proliferation and survival of basal epithelial cells and is over-expressed in NPC tumors. Here we show that ΔNp63α promotes EBV latency by inhibiting activation of the BZLF1 IE promoter (Zp). Furthermore, we find that another p63 gene splice variant, TAp63α, which is expressed in some Burkitt and diffuse large B cell lymphomas, also represses EBV lytic reactivation. We demonstrate that ΔNp63α inhibits the Z promoter indirectly by preventing the ability of other transcription factors, including the viral IE R protein and the cellular KLF4 protein, to activate Zp. Mechanistically, we show that ΔNp63α promotes viral latency in undifferentiated epithelial cells both by enhancing expression of a known Zp repressor protein, c-myc, and by decreasing cellular p38 kinase activity. Furthermore, we find that the ability of cis-platinum chemotherapy to degrade ΔNp63α contributes to the lytic-inducing effect of this agent in EBV-infected epithelial cells. Together these findings demonstrate that the loss of ΔNp63α expression, in conjunction with enhanced expression of differentiation-dependent transcription factors such as BLIMP1 and KLF4, induces lytic EBV reactivation during normal epithelial cell differentiation. Conversely, expression of ΔNp63α in undifferentiated nasopharyngeal carcinoma cells and TAp63α in Burkitt lymphoma promotes EBV latency in these malignancies. Public Library of Science 2021-11-08 /pmc/articles/PMC8601603/ /pubmed/34748616 http://dx.doi.org/10.1371/journal.ppat.1010045 Text en © 2021 Van Sciver et al https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Van Sciver, Nicholas
Ohashi, Makoto
Nawandar, Dhananjay M.
Pauly, Nicholas P.
Lee, Denis
Makielski, Kathleen R.
Bristol, Jillian A.
Tsao, Sai Wah
Lambert, Paul F.
Johannsen, Eric C.
Kenney, Shannon C.
ΔNp63α promotes Epstein-Barr virus latency in undifferentiated epithelial cells
title ΔNp63α promotes Epstein-Barr virus latency in undifferentiated epithelial cells
title_full ΔNp63α promotes Epstein-Barr virus latency in undifferentiated epithelial cells
title_fullStr ΔNp63α promotes Epstein-Barr virus latency in undifferentiated epithelial cells
title_full_unstemmed ΔNp63α promotes Epstein-Barr virus latency in undifferentiated epithelial cells
title_short ΔNp63α promotes Epstein-Barr virus latency in undifferentiated epithelial cells
title_sort δnp63α promotes epstein-barr virus latency in undifferentiated epithelial cells
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8601603/
https://www.ncbi.nlm.nih.gov/pubmed/34748616
http://dx.doi.org/10.1371/journal.ppat.1010045
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