The Epstein-Barr virus deubiquitinating enzyme BPLF1 regulates the activity of topoisomerase II during productive infection.

Topoisomerases are essential for the replication of herpesviruses but the mechanisms by which the viruses hijack the cellular enzymes are largely unknown. We found that topoisomerase-II (TOP2) is a substrate of the Epstein-Barr virus (EBV) ubiquitin deconjugase BPLF1. BPLF1 co-immunoprecipitated and...

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Autores principales:	Jinlin Li, Noemi Nagy, Jiangnan Liu, Soham Gupta, Teresa Frisan, Thomas Hennig, Donald P Cameron, Laura Baranello, Maria G Masucci
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/19987ba58b534c27bc4d47f405f3f9d1
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spelling	oai:doaj.org-article:19987ba58b534c27bc4d47f405f3f9d12021-12-02T20:00:09ZThe Epstein-Barr virus deubiquitinating enzyme BPLF1 regulates the activity of topoisomerase II during productive infection.1553-73661553-737410.1371/journal.ppat.1009954https://doaj.org/article/19987ba58b534c27bc4d47f405f3f9d12021-09-01T00:00:00Zhttps://doi.org/10.1371/journal.ppat.1009954https://doaj.org/toc/1553-7366https://doaj.org/toc/1553-7374Topoisomerases are essential for the replication of herpesviruses but the mechanisms by which the viruses hijack the cellular enzymes are largely unknown. We found that topoisomerase-II (TOP2) is a substrate of the Epstein-Barr virus (EBV) ubiquitin deconjugase BPLF1. BPLF1 co-immunoprecipitated and deubiquitinated TOP2, and stabilized SUMOylated TOP2 trapped in cleavage complexes (TOP2ccs), which halted the DNA damage response to TOP2-induced double strand DNA breaks and promoted cell survival. Induction of the productive virus cycle in epithelial and lymphoid cell lines carrying recombinant EBV encoding the active enzyme was accompanied by TOP2 deubiquitination, accumulation of TOP2ccs and resistance to Etoposide toxicity. The protective effect of BPLF1 was dependent on the expression of tyrosyl-DNA phosphodiesterase 2 (TDP2) that releases DNA-trapped TOP2 and promotes error-free DNA repair. These findings highlight a previously unrecognized function of BPLF1 in supporting a non-proteolytic pathway for TOP2ccs debulking that favors cell survival and virus production.Jinlin LiNoemi NagyJiangnan LiuSoham GuptaTeresa FrisanThomas HennigDonald P CameronLaura BaranelloMaria G MasucciPublic Library of Science (PLoS)articleImmunologic diseases. AllergyRC581-607Biology (General)QH301-705.5ENPLoS Pathogens, Vol 17, Iss 9, p e1009954 (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 Jinlin Li Noemi Nagy Jiangnan Liu Soham Gupta Teresa Frisan Thomas Hennig Donald P Cameron Laura Baranello Maria G Masucci The Epstein-Barr virus deubiquitinating enzyme BPLF1 regulates the activity of topoisomerase II during productive infection.
description	Topoisomerases are essential for the replication of herpesviruses but the mechanisms by which the viruses hijack the cellular enzymes are largely unknown. We found that topoisomerase-II (TOP2) is a substrate of the Epstein-Barr virus (EBV) ubiquitin deconjugase BPLF1. BPLF1 co-immunoprecipitated and deubiquitinated TOP2, and stabilized SUMOylated TOP2 trapped in cleavage complexes (TOP2ccs), which halted the DNA damage response to TOP2-induced double strand DNA breaks and promoted cell survival. Induction of the productive virus cycle in epithelial and lymphoid cell lines carrying recombinant EBV encoding the active enzyme was accompanied by TOP2 deubiquitination, accumulation of TOP2ccs and resistance to Etoposide toxicity. The protective effect of BPLF1 was dependent on the expression of tyrosyl-DNA phosphodiesterase 2 (TDP2) that releases DNA-trapped TOP2 and promotes error-free DNA repair. These findings highlight a previously unrecognized function of BPLF1 in supporting a non-proteolytic pathway for TOP2ccs debulking that favors cell survival and virus production.
format	article
author	Jinlin Li Noemi Nagy Jiangnan Liu Soham Gupta Teresa Frisan Thomas Hennig Donald P Cameron Laura Baranello Maria G Masucci
author_facet	Jinlin Li Noemi Nagy Jiangnan Liu Soham Gupta Teresa Frisan Thomas Hennig Donald P Cameron Laura Baranello Maria G Masucci
author_sort	Jinlin Li
title	The Epstein-Barr virus deubiquitinating enzyme BPLF1 regulates the activity of topoisomerase II during productive infection.
title_short	The Epstein-Barr virus deubiquitinating enzyme BPLF1 regulates the activity of topoisomerase II during productive infection.
title_full	The Epstein-Barr virus deubiquitinating enzyme BPLF1 regulates the activity of topoisomerase II during productive infection.
title_fullStr	The Epstein-Barr virus deubiquitinating enzyme BPLF1 regulates the activity of topoisomerase II during productive infection.
title_full_unstemmed	The Epstein-Barr virus deubiquitinating enzyme BPLF1 regulates the activity of topoisomerase II during productive infection.
title_sort	epstein-barr virus deubiquitinating enzyme bplf1 regulates the activity of topoisomerase ii during productive infection.
publisher	Public Library of Science (PLoS)
publishDate	2021
url	https://doaj.org/article/19987ba58b534c27bc4d47f405f3f9d1
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The Epstein-Barr virus deubiquitinating enzyme BPLF1 regulates the activity of topoisomerase II during productive infection.

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