Viral DNA Binding Protein SUMOylation Promotes PML Nuclear Body Localization Next to Viral Replication Centers

ABSTRACT Human adenoviruses (HAdVs) have developed mechanisms to manipulate cellular antiviral measures to ensure proper DNA replication, with detailed processes far from being understood. Host cells repress incoming viral genomes through a network of transcriptional regulators that normally control...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Miona Stubbe, Julia Mai, Christina Paulus, Hans Christian Stubbe, Julia Berscheminski, Maryam Karimi, Samuel Hofmann, Elisabeth Weber, Kamyar Hadian, Ron Hay, Peter Groitl, Michael Nevels, Thomas Dobner, Sabrina Schreiner
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2020
Materias:	DNA binding protein E2A/DBP HAdV human adenovirus PML-NB SUMO Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/d784e1e6eba148b3a70d9bc1131bb912
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:d784e1e6eba148b3a70d9bc1131bb912
record_format	dspace
spelling	oai:doaj.org-article:d784e1e6eba148b3a70d9bc1131bb9122021-11-15T15:57:02ZViral DNA Binding Protein SUMOylation Promotes PML Nuclear Body Localization Next to Viral Replication Centers10.1128/mBio.00049-202150-7511https://doaj.org/article/d784e1e6eba148b3a70d9bc1131bb9122020-04-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.00049-20https://doaj.org/toc/2150-7511ABSTRACT Human adenoviruses (HAdVs) have developed mechanisms to manipulate cellular antiviral measures to ensure proper DNA replication, with detailed processes far from being understood. Host cells repress incoming viral genomes through a network of transcriptional regulators that normally control cellular homeostasis. The nuclear domains involved are promyelocytic leukemia protein nuclear bodies (PML-NBs), interferon-inducible, dot-like nuclear structures and hot spots of SUMO posttranslational modification (PTM). In HAdV-infected cells, such SUMO factories are found in close proximity to newly established viral replication centers (RCs) marked by the adenoviral DNA binding protein (DBP) E2A. Here, we show that E2A is a novel target of host SUMOylation, leading to PTMs supporting E2A function in promoting productive infection. Our data show that SUMOylated E2A interacts with PML. Decreasing SUMO-E2A protein levels by generating HAdV variants mutated in the three main SUMO conjugation motifs (SCMs) led to lower numbers of viral RCs and PML-NBs, and these two structures were no longer next to each other. Our data further indicate that SUMOylated E2A binds the host transcription factor Sp100A, promoting HAdV gene expression, and represents the molecular bridge between PML tracks and adjacent viral RCs. Consequently, E2A SCM mutations repressed late viral gene expression and progeny production. These data highlight a novel mechanism used by the virus to benefit from host antiviral responses by exploiting the cellular SUMO conjugation machinery. IMPORTANCE PML nuclear bodies (PML-NBs) are implicated in general antiviral defense based on recruiting host restriction factors; however, it is not understood so far why viruses would establish viral replication centers (RCs) juxtaposed to such “antiviral” compartments. To understand this enigma, we investigate the cross talk between PML-NB components and viral RCs to find the missing link connecting both compartments to promote efficient viral replication and gene expression. Taken together, the current concept is more intricate than originally believed, since viruses apparently take advantage of several specific PML-NB-associated proteins to promote productive infection. Simultaneously, they efficiently inhibit antiviral measures to maintain the viral infectious program. Our data provide evidence that SUMOylation of the viral RC marker protein E2A represents the basis of this virus-host interface and regulates various downstream events to support HAdV productive infection. These results are the basis of our current attempts to generate and screen for specific E2A SUMOylation inhibitors to constitute novel therapeutic approaches to limit and prevent HAdV-mediated diseases and mortality of immunosuppressed patients.Miona StubbeJulia MaiChristina PaulusHans Christian StubbeJulia BerscheminskiMaryam KarimiSamuel HofmannElisabeth WeberKamyar HadianRon HayPeter GroitlMichael NevelsThomas DobnerSabrina SchreinerAmerican Society for MicrobiologyarticleDNA binding proteinE2A/DBPHAdVhuman adenovirusPML-NBSUMOMicrobiologyQR1-502ENmBio, Vol 11, Iss 2 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	DNA binding protein E2A/DBP HAdV human adenovirus PML-NB SUMO Microbiology QR1-502
spellingShingle	DNA binding protein E2A/DBP HAdV human adenovirus PML-NB SUMO Microbiology QR1-502 Miona Stubbe Julia Mai Christina Paulus Hans Christian Stubbe Julia Berscheminski Maryam Karimi Samuel Hofmann Elisabeth Weber Kamyar Hadian Ron Hay Peter Groitl Michael Nevels Thomas Dobner Sabrina Schreiner Viral DNA Binding Protein SUMOylation Promotes PML Nuclear Body Localization Next to Viral Replication Centers
description	ABSTRACT Human adenoviruses (HAdVs) have developed mechanisms to manipulate cellular antiviral measures to ensure proper DNA replication, with detailed processes far from being understood. Host cells repress incoming viral genomes through a network of transcriptional regulators that normally control cellular homeostasis. The nuclear domains involved are promyelocytic leukemia protein nuclear bodies (PML-NBs), interferon-inducible, dot-like nuclear structures and hot spots of SUMO posttranslational modification (PTM). In HAdV-infected cells, such SUMO factories are found in close proximity to newly established viral replication centers (RCs) marked by the adenoviral DNA binding protein (DBP) E2A. Here, we show that E2A is a novel target of host SUMOylation, leading to PTMs supporting E2A function in promoting productive infection. Our data show that SUMOylated E2A interacts with PML. Decreasing SUMO-E2A protein levels by generating HAdV variants mutated in the three main SUMO conjugation motifs (SCMs) led to lower numbers of viral RCs and PML-NBs, and these two structures were no longer next to each other. Our data further indicate that SUMOylated E2A binds the host transcription factor Sp100A, promoting HAdV gene expression, and represents the molecular bridge between PML tracks and adjacent viral RCs. Consequently, E2A SCM mutations repressed late viral gene expression and progeny production. These data highlight a novel mechanism used by the virus to benefit from host antiviral responses by exploiting the cellular SUMO conjugation machinery. IMPORTANCE PML nuclear bodies (PML-NBs) are implicated in general antiviral defense based on recruiting host restriction factors; however, it is not understood so far why viruses would establish viral replication centers (RCs) juxtaposed to such “antiviral” compartments. To understand this enigma, we investigate the cross talk between PML-NB components and viral RCs to find the missing link connecting both compartments to promote efficient viral replication and gene expression. Taken together, the current concept is more intricate than originally believed, since viruses apparently take advantage of several specific PML-NB-associated proteins to promote productive infection. Simultaneously, they efficiently inhibit antiviral measures to maintain the viral infectious program. Our data provide evidence that SUMOylation of the viral RC marker protein E2A represents the basis of this virus-host interface and regulates various downstream events to support HAdV productive infection. These results are the basis of our current attempts to generate and screen for specific E2A SUMOylation inhibitors to constitute novel therapeutic approaches to limit and prevent HAdV-mediated diseases and mortality of immunosuppressed patients.
format	article
author	Miona Stubbe Julia Mai Christina Paulus Hans Christian Stubbe Julia Berscheminski Maryam Karimi Samuel Hofmann Elisabeth Weber Kamyar Hadian Ron Hay Peter Groitl Michael Nevels Thomas Dobner Sabrina Schreiner
author_facet	Miona Stubbe Julia Mai Christina Paulus Hans Christian Stubbe Julia Berscheminski Maryam Karimi Samuel Hofmann Elisabeth Weber Kamyar Hadian Ron Hay Peter Groitl Michael Nevels Thomas Dobner Sabrina Schreiner
author_sort	Miona Stubbe
title	Viral DNA Binding Protein SUMOylation Promotes PML Nuclear Body Localization Next to Viral Replication Centers
title_short	Viral DNA Binding Protein SUMOylation Promotes PML Nuclear Body Localization Next to Viral Replication Centers
title_full	Viral DNA Binding Protein SUMOylation Promotes PML Nuclear Body Localization Next to Viral Replication Centers
title_fullStr	Viral DNA Binding Protein SUMOylation Promotes PML Nuclear Body Localization Next to Viral Replication Centers
title_full_unstemmed	Viral DNA Binding Protein SUMOylation Promotes PML Nuclear Body Localization Next to Viral Replication Centers
title_sort	viral dna binding protein sumoylation promotes pml nuclear body localization next to viral replication centers
publisher	American Society for Microbiology
publishDate	2020
url	https://doaj.org/article/d784e1e6eba148b3a70d9bc1131bb912
work_keys_str_mv	AT mionastubbe viraldnabindingproteinsumoylationpromotespmlnuclearbodylocalizationnexttoviralreplicationcenters AT juliamai viraldnabindingproteinsumoylationpromotespmlnuclearbodylocalizationnexttoviralreplicationcenters AT christinapaulus viraldnabindingproteinsumoylationpromotespmlnuclearbodylocalizationnexttoviralreplicationcenters AT hanschristianstubbe viraldnabindingproteinsumoylationpromotespmlnuclearbodylocalizationnexttoviralreplicationcenters AT juliaberscheminski viraldnabindingproteinsumoylationpromotespmlnuclearbodylocalizationnexttoviralreplicationcenters AT maryamkarimi viraldnabindingproteinsumoylationpromotespmlnuclearbodylocalizationnexttoviralreplicationcenters AT samuelhofmann viraldnabindingproteinsumoylationpromotespmlnuclearbodylocalizationnexttoviralreplicationcenters AT elisabethweber viraldnabindingproteinsumoylationpromotespmlnuclearbodylocalizationnexttoviralreplicationcenters AT kamyarhadian viraldnabindingproteinsumoylationpromotespmlnuclearbodylocalizationnexttoviralreplicationcenters AT ronhay viraldnabindingproteinsumoylationpromotespmlnuclearbodylocalizationnexttoviralreplicationcenters AT petergroitl viraldnabindingproteinsumoylationpromotespmlnuclearbodylocalizationnexttoviralreplicationcenters AT michaelnevels viraldnabindingproteinsumoylationpromotespmlnuclearbodylocalizationnexttoviralreplicationcenters AT thomasdobner viraldnabindingproteinsumoylationpromotespmlnuclearbodylocalizationnexttoviralreplicationcenters AT sabrinaschreiner viraldnabindingproteinsumoylationpromotespmlnuclearbodylocalizationnexttoviralreplicationcenters
_version_	1718427057476599808

Viral DNA Binding Protein SUMOylation Promotes PML Nuclear Body Localization Next to Viral Replication Centers

Ejemplares similares