Cytomegalovirus immediate-early 1 proteins form a structurally distinct protein class with adaptations determining cross-species barriers.

Restriction factors are potent antiviral proteins that constitute a first line of intracellular defense by blocking viral replication and spread. During co-evolution, however, viruses have developed antagonistic proteins to modulate or degrade the restriction factors of their host. To ensure the suc...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Johannes Schweininger, Myriam Scherer, Franziska Rothemund, Eva-Maria Schilling, Sonja Wörz, Thomas Stamminger, Yves A Muller
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/77fb03220dbd48e8b450e0768989907b
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:77fb03220dbd48e8b450e0768989907b
record_format	dspace
spelling	oai:doaj.org-article:77fb03220dbd48e8b450e0768989907b2021-12-02T20:00:17ZCytomegalovirus immediate-early 1 proteins form a structurally distinct protein class with adaptations determining cross-species barriers.1553-73661553-737410.1371/journal.ppat.1009863https://doaj.org/article/77fb03220dbd48e8b450e0768989907b2021-08-01T00:00:00Zhttps://doi.org/10.1371/journal.ppat.1009863https://doaj.org/toc/1553-7366https://doaj.org/toc/1553-7374Restriction factors are potent antiviral proteins that constitute a first line of intracellular defense by blocking viral replication and spread. During co-evolution, however, viruses have developed antagonistic proteins to modulate or degrade the restriction factors of their host. To ensure the success of lytic replication, the herpesvirus human cytomegalovirus (HCMV) expresses the immediate-early protein IE1, which acts as an antagonist of antiviral, subnuclear structures termed PML nuclear bodies (PML-NBs). IE1 interacts directly with PML, the key protein of PML-NBs, through its core domain and disrupts the dot-like multiprotein complexes thereby abrogating the antiviral effects. Here we present the crystal structures of the human and rat cytomegalovirus core domain (IE1CORE). We found that IE1CORE domains, also including the previously characterized IE1CORE of rhesus CMV, form a distinct class of proteins that are characterized by a highly similar and unique tertiary fold and quaternary assembly. This contrasts to a marked amino acid sequence diversity suggesting that strong positive selection evolved a conserved fold, while immune selection pressure may have fostered sequence divergence of IE1. At the same time, we detected specific differences in the helix arrangements of primate versus rodent IE1CORE structures. Functional characterization revealed a conserved mechanism of PML-NB disruption, however, primate and rodent IE1 proteins were only effective in cells of the natural host species but not during cross-species infection. Remarkably, we observed that expression of HCMV IE1 allows rat cytomegalovirus replication in human cells. We conclude that cytomegaloviruses have evolved a distinct protein tertiary structure of IE1 to effectively bind and inactivate an important cellular restriction factor. Furthermore, our data show that the IE1 fold has been adapted to maximize the efficacy of PML targeting in a species-specific manner and support the concept that the PML-NBs-based intrinsic defense constitutes a barrier to cross-species transmission of HCMV.Johannes SchweiningerMyriam SchererFranziska RothemundEva-Maria SchillingSonja WörzThomas StammingerYves A MullerPublic Library of Science (PLoS)articleImmunologic diseases. AllergyRC581-607Biology (General)QH301-705.5ENPLoS Pathogens, Vol 17, Iss 8, p e1009863 (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 Johannes Schweininger Myriam Scherer Franziska Rothemund Eva-Maria Schilling Sonja Wörz Thomas Stamminger Yves A Muller Cytomegalovirus immediate-early 1 proteins form a structurally distinct protein class with adaptations determining cross-species barriers.
description	Restriction factors are potent antiviral proteins that constitute a first line of intracellular defense by blocking viral replication and spread. During co-evolution, however, viruses have developed antagonistic proteins to modulate or degrade the restriction factors of their host. To ensure the success of lytic replication, the herpesvirus human cytomegalovirus (HCMV) expresses the immediate-early protein IE1, which acts as an antagonist of antiviral, subnuclear structures termed PML nuclear bodies (PML-NBs). IE1 interacts directly with PML, the key protein of PML-NBs, through its core domain and disrupts the dot-like multiprotein complexes thereby abrogating the antiviral effects. Here we present the crystal structures of the human and rat cytomegalovirus core domain (IE1CORE). We found that IE1CORE domains, also including the previously characterized IE1CORE of rhesus CMV, form a distinct class of proteins that are characterized by a highly similar and unique tertiary fold and quaternary assembly. This contrasts to a marked amino acid sequence diversity suggesting that strong positive selection evolved a conserved fold, while immune selection pressure may have fostered sequence divergence of IE1. At the same time, we detected specific differences in the helix arrangements of primate versus rodent IE1CORE structures. Functional characterization revealed a conserved mechanism of PML-NB disruption, however, primate and rodent IE1 proteins were only effective in cells of the natural host species but not during cross-species infection. Remarkably, we observed that expression of HCMV IE1 allows rat cytomegalovirus replication in human cells. We conclude that cytomegaloviruses have evolved a distinct protein tertiary structure of IE1 to effectively bind and inactivate an important cellular restriction factor. Furthermore, our data show that the IE1 fold has been adapted to maximize the efficacy of PML targeting in a species-specific manner and support the concept that the PML-NBs-based intrinsic defense constitutes a barrier to cross-species transmission of HCMV.
format	article
author	Johannes Schweininger Myriam Scherer Franziska Rothemund Eva-Maria Schilling Sonja Wörz Thomas Stamminger Yves A Muller
author_facet	Johannes Schweininger Myriam Scherer Franziska Rothemund Eva-Maria Schilling Sonja Wörz Thomas Stamminger Yves A Muller
author_sort	Johannes Schweininger
title	Cytomegalovirus immediate-early 1 proteins form a structurally distinct protein class with adaptations determining cross-species barriers.
title_short	Cytomegalovirus immediate-early 1 proteins form a structurally distinct protein class with adaptations determining cross-species barriers.
title_full	Cytomegalovirus immediate-early 1 proteins form a structurally distinct protein class with adaptations determining cross-species barriers.
title_fullStr	Cytomegalovirus immediate-early 1 proteins form a structurally distinct protein class with adaptations determining cross-species barriers.
title_full_unstemmed	Cytomegalovirus immediate-early 1 proteins form a structurally distinct protein class with adaptations determining cross-species barriers.
title_sort	cytomegalovirus immediate-early 1 proteins form a structurally distinct protein class with adaptations determining cross-species barriers.
publisher	Public Library of Science (PLoS)
publishDate	2021
url	https://doaj.org/article/77fb03220dbd48e8b450e0768989907b
work_keys_str_mv	AT johannesschweininger cytomegalovirusimmediateearly1proteinsformastructurallydistinctproteinclasswithadaptationsdeterminingcrossspeciesbarriers AT myriamscherer cytomegalovirusimmediateearly1proteinsformastructurallydistinctproteinclasswithadaptationsdeterminingcrossspeciesbarriers AT franziskarothemund cytomegalovirusimmediateearly1proteinsformastructurallydistinctproteinclasswithadaptationsdeterminingcrossspeciesbarriers AT evamariaschilling cytomegalovirusimmediateearly1proteinsformastructurallydistinctproteinclasswithadaptationsdeterminingcrossspeciesbarriers AT sonjaworz cytomegalovirusimmediateearly1proteinsformastructurallydistinctproteinclasswithadaptationsdeterminingcrossspeciesbarriers AT thomasstamminger cytomegalovirusimmediateearly1proteinsformastructurallydistinctproteinclasswithadaptationsdeterminingcrossspeciesbarriers AT yvesamuller cytomegalovirusimmediateearly1proteinsformastructurallydistinctproteinclasswithadaptationsdeterminingcrossspeciesbarriers
_version_	1718375730208833536

Cytomegalovirus immediate-early 1 proteins form a structurally distinct protein class with adaptations determining cross-species barriers.

Ejemplares similares