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:	Nicholas Van Sciver, Makoto Ohashi, Dhananjay M. Nawandar, Nicholas P. Pauly, Denis Lee, Kathleen R. Makielski, Jillian A. Bristol, Sai Wah Tsao, Paul F. Lambert, Eric C. Johannsen, Shannon C. Kenney
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2021
Materias:	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/cf1e2f37626547988264e0a8c5e31e20
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spelling	oai:doaj.org-article:cf1e2f37626547988264e0a8c5e31e202021-11-25T05:46:51ZΔNp63α promotes Epstein-Barr virus latency in undifferentiated epithelial cells1553-73661553-7374https://doaj.org/article/cf1e2f37626547988264e0a8c5e31e202021-11-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC8601603/?tool=EBIhttps://doaj.org/toc/1553-7366https://doaj.org/toc/1553-7374Epstein-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. Author summary Epstein-Barr virus (EBV) is an important cause of both epithelial cell and B cell human cancers. EBV-infected tumors have predominantly latent viral infection, allowing them to escape the cell killing that occurs during lytic viral infection. EBV is highly lytic in normal differentiated oral epithelial cells. Thus, an important question is how the virus maintains the latent form of viral infection in EBV-associated epithelial cell tumors such as undifferentiated nasopharyngeal carcinoma (NPC). This study demonstrates that the cellular transcription factor ΔNp63ɑ, which is specifically expressed in undifferentiated basal epithelial cells and is over-expressed in NPC tumors, maintains EBV latency by inhibiting the activity of the viral immediate-early (IE) promoter (Zp) that drives expression of the BZLF1 IE protein. A related splice variant, TAp63α, found in some EBV+ lymphomas, has a similar inhibitory effect. Our findings reveal that ΔNp63ɑ and TAp63α contribute to EBV latency in both epithelial and B cell tumors. Furthermore, since differentiation results in loss of ΔNp63ɑ expression, our results help to explain why lytic EBV reactivation is promoted by epithelial cell differentiation.Nicholas Van SciverMakoto OhashiDhananjay M. NawandarNicholas P. PaulyDenis LeeKathleen R. MakielskiJillian A. BristolSai Wah TsaoPaul F. LambertEric C. JohannsenShannon C. KenneyPublic Library of Science (PLoS)articleImmunologic diseases. AllergyRC581-607Biology (General)QH301-705.5ENPLoS Pathogens, Vol 17, Iss 11 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5
spellingShingle	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5 Nicholas Van Sciver Makoto Ohashi Dhananjay M. Nawandar Nicholas P. Pauly Denis Lee Kathleen R. Makielski Jillian A. Bristol Sai Wah Tsao Paul F. Lambert Eric C. Johannsen Shannon C. Kenney ΔNp63α promotes Epstein-Barr virus latency in undifferentiated epithelial cells
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. Author summary Epstein-Barr virus (EBV) is an important cause of both epithelial cell and B cell human cancers. EBV-infected tumors have predominantly latent viral infection, allowing them to escape the cell killing that occurs during lytic viral infection. EBV is highly lytic in normal differentiated oral epithelial cells. Thus, an important question is how the virus maintains the latent form of viral infection in EBV-associated epithelial cell tumors such as undifferentiated nasopharyngeal carcinoma (NPC). This study demonstrates that the cellular transcription factor ΔNp63ɑ, which is specifically expressed in undifferentiated basal epithelial cells and is over-expressed in NPC tumors, maintains EBV latency by inhibiting the activity of the viral immediate-early (IE) promoter (Zp) that drives expression of the BZLF1 IE protein. A related splice variant, TAp63α, found in some EBV+ lymphomas, has a similar inhibitory effect. Our findings reveal that ΔNp63ɑ and TAp63α contribute to EBV latency in both epithelial and B cell tumors. Furthermore, since differentiation results in loss of ΔNp63ɑ expression, our results help to explain why lytic EBV reactivation is promoted by epithelial cell differentiation.
format	article
author	Nicholas Van Sciver Makoto Ohashi Dhananjay M. Nawandar Nicholas P. Pauly Denis Lee Kathleen R. Makielski Jillian A. Bristol Sai Wah Tsao Paul F. Lambert Eric C. Johannsen Shannon C. Kenney
author_facet	Nicholas Van Sciver Makoto Ohashi Dhananjay M. Nawandar Nicholas P. Pauly Denis Lee Kathleen R. Makielski Jillian A. Bristol Sai Wah Tsao Paul F. Lambert Eric C. Johannsen Shannon C. Kenney
author_sort	Nicholas Van Sciver
title	ΔNp63α promotes Epstein-Barr virus latency in undifferentiated epithelial cells
title_short	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_sort	δnp63α promotes epstein-barr virus latency in undifferentiated epithelial cells
publisher	Public Library of Science (PLoS)
publishDate	2021
url	https://doaj.org/article/cf1e2f37626547988264e0a8c5e31e20
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ΔNp63α promotes Epstein-Barr virus latency in undifferentiated epithelial cells

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