Cargando…
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...
Autores principales: | , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2021
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8376021/ https://www.ncbi.nlm.nih.gov/pubmed/34370791 http://dx.doi.org/10.1371/journal.ppat.1009863 |
_version_ | 1783740422213861376 |
---|---|
author | Schweininger, Johannes Scherer, Myriam Rothemund, Franziska Schilling, Eva-Maria Wörz, Sonja Stamminger, Thomas Muller, Yves A. |
author_facet | Schweininger, Johannes Scherer, Myriam Rothemund, Franziska Schilling, Eva-Maria Wörz, Sonja Stamminger, Thomas Muller, Yves A. |
author_sort | Schweininger, Johannes |
collection | PubMed |
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 (IE1(CORE)). We found that IE1(CORE) domains, also including the previously characterized IE1(CORE) 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 IE1(CORE) 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 | Online Article Text |
id | pubmed-8376021 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-83760212021-08-20 Cytomegalovirus immediate-early 1 proteins form a structurally distinct protein class with adaptations determining cross-species barriers Schweininger, Johannes Scherer, Myriam Rothemund, Franziska Schilling, Eva-Maria Wörz, Sonja Stamminger, Thomas Muller, Yves A. PLoS Pathog Research Article 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 (IE1(CORE)). We found that IE1(CORE) domains, also including the previously characterized IE1(CORE) 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 IE1(CORE) 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. Public Library of Science 2021-08-09 /pmc/articles/PMC8376021/ /pubmed/34370791 http://dx.doi.org/10.1371/journal.ppat.1009863 Text en © 2021 Schweininger 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 Schweininger, Johannes Scherer, Myriam Rothemund, Franziska Schilling, Eva-Maria Wörz, Sonja Stamminger, Thomas Muller, Yves A. Cytomegalovirus immediate-early 1 proteins form a structurally distinct protein class with adaptations determining cross-species barriers |
title | 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_short | 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 |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8376021/ https://www.ncbi.nlm.nih.gov/pubmed/34370791 http://dx.doi.org/10.1371/journal.ppat.1009863 |
work_keys_str_mv | AT schweiningerjohannes cytomegalovirusimmediateearly1proteinsformastructurallydistinctproteinclasswithadaptationsdeterminingcrossspeciesbarriers AT scherermyriam cytomegalovirusimmediateearly1proteinsformastructurallydistinctproteinclasswithadaptationsdeterminingcrossspeciesbarriers AT rothemundfranziska cytomegalovirusimmediateearly1proteinsformastructurallydistinctproteinclasswithadaptationsdeterminingcrossspeciesbarriers AT schillingevamaria cytomegalovirusimmediateearly1proteinsformastructurallydistinctproteinclasswithadaptationsdeterminingcrossspeciesbarriers AT worzsonja cytomegalovirusimmediateearly1proteinsformastructurallydistinctproteinclasswithadaptationsdeterminingcrossspeciesbarriers AT stammingerthomas cytomegalovirusimmediateearly1proteinsformastructurallydistinctproteinclasswithadaptationsdeterminingcrossspeciesbarriers AT mulleryvesa cytomegalovirusimmediateearly1proteinsformastructurallydistinctproteinclasswithadaptationsdeterminingcrossspeciesbarriers |