The Abundant Tegument Protein pUL25 of Human Cytomegalovirus Prevents Proteasomal Degradation of pUL26 and Supports Its Suppression of ISGylation

Publication type:
Journal article
Metadata:
Autoren
  • Christine Zimmermann
  • Nicole Buescher
  • Steffi Krauter
  • Nadine Kraemer
  • Uwe Wolfrum
  • Elisabeth Sehn
  • Stefan Tenzer
  • Bodo Plachter
Autoren-URL
https://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=fis-test-1&SrcAuth=WosAPI&KeyUT=WOS:000451336900010&DestLinkType=FullRecord&DestApp=WOS_CPL
DOI
10.1128/JVI.01180-18
eISSN
1098-5514
Externe Identifier
  • Clarivate Analytics Document Solution ID: HB8KE
  • PubMed Identifier: 30282718
ISSN
0022-538X
Ausgabe der Veröffentlichung
24
Zeitschrift
JOURNAL OF VIROLOGY
Schlüsselwörter
  • dense bodies
  • ISG15
  • ISGylation
  • cytomegalovirus
  • pUL25
  • pUL26
  • pp65
  • tegument
Artikelnummer
ARTN e01180-18
Datum der Veröffentlichung
2018
Status
Published
Titel
The Abundant Tegument Protein pUL25 of Human Cytomegalovirus Prevents Proteasomal Degradation of pUL26 and Supports Its Suppression of ISGylation
Sub types
  • Article
Ausgabe der Zeitschrift
92

Data source: Web of Science (Lite)

Other metadata sources:
Abstract
<jats:p>Human cytomegalovirus (HCMV) expresses a number of tegument proteins that interfere with the intrinsic and the innate defense mechanisms of the cell. Initial induction of the interferon-stimulated gene 15 protein (ISG15) and conjugation of proteins with ISG15 (ISGylation) by HCMV infection are subsequently attenuated by the expression of the viral IE1, pUL50, and pUL26 proteins. This study adds pUL25 as another factor that contributes to suppression of ISGylation. The tegument protein interacts with pUL26 and prevents its degradation by the proteasome. By doing this, it supports its restrictive influence on ISGylation. In addition, a lack of pUL25 enhances the levels of free ISG15, indicating that the tegument protein may interfere with the interferon response on levels other than interacting with pUL26. Knowledge obtained in this study widens our understanding of HCMV immune evasion and may also provide a new avenue for the use of pUL25-negative strains for vaccine production.</jats:p>
Autoren
  • Christine Zimmermann
  • Nicole Büscher
  • Steffi Krauter
  • Nadine Krämer
  • Uwe Wolfrum
  • Elisabeth Sehn
  • Stefan Tenzer
  • Bodo Plachter
DOI
10.1128/jvi.01180-18
Editoren
  • Rozanne M Sandri-Goldin
eISSN
1098-5514
ISSN
0022-538X
Ausgabe der Veröffentlichung
24
Zeitschrift
Journal of Virology
Sprache
en
Datum der Veröffentlichung
2018
Status
Published
Herausgeber
American Society for Microbiology
Herausgeber URL
http://dx.doi.org/10.1128/jvi.01180-18
Datum der Datenerfassung
2022
Titel
The Abundant Tegument Protein pUL25 of Human Cytomegalovirus Prevents Proteasomal Degradation of pUL26 and Supports Its Suppression of ISGylation
Ausgabe der Zeitschrift
92

Data source: Crossref

Abstract
The tegument of human cytomegalovirus (HCMV) virions contains proteins that interfere with both the intrinsic and the innate immunity. One protein with a thus far unknown function is pUL25. The deletion of pUL25 in a viral mutant (Towne-ΔUL25) had no impact on the release of virions and subviral dense bodies or on virion morphogenesis. Proteomic analyses showed few alterations in the overall protein composition of extracellular particles. A surprising result, however, was the almost complete absence of pUL26 in virions and dense bodies of Towne-ΔUL25 and a reduction of the large isoform pUL26-p27 in mutant virus-infected cells. pUL26 had been shown to inhibit protein conjugation with the interferon-stimulated gene 15 protein (ISG15), thereby supporting HCMV replication. To test for a functional relationship between pUL25 and pUL26, we addressed the steady-state levels of pUL26 and found them to be reduced in Towne-ΔUL25-infected cells. Coimmunoprecipitation experiments proved an interaction between pUL25 and pUL26. Surprisingly, the overall protein ISGylation was enhanced in Towne-ΔUL25-infected cells, thus mimicking the phenotype of a pUL26-deleted HCMV mutant. The functional relevance of this was confirmed by showing that the replication of Towne-ΔUL25 was more sensitive to beta interferon. The increase of protein ISGylation was also seen in cells infected with a mutant lacking the tegument protein pp65. Upon retesting, we found that pUL26 degradation was also increased when pp65 was unavailable. Our experiments show that both pUL25 and pp65 regulate pUL26 degradation and the pUL26-dependent reduction of ISGylation and add pUL25 as another HCMV tegument protein that interferes with the intrinsic immunity of the host cell.<b>IMPORTANCE</b> Human cytomegalovirus (HCMV) expresses a number of tegument proteins that interfere with the intrinsic and the innate defense mechanisms of the cell. Initial induction of the interferon-stimulated gene 15 protein (ISG15) and conjugation of proteins with ISG15 (ISGylation) by HCMV infection are subsequently attenuated by the expression of the viral IE1, pUL50, and pUL26 proteins. This study adds pUL25 as another factor that contributes to suppression of ISGylation. The tegument protein interacts with pUL26 and prevents its degradation by the proteasome. By doing this, it supports its restrictive influence on ISGylation. In addition, a lack of pUL25 enhances the levels of free ISG15, indicating that the tegument protein may interfere with the interferon response on levels other than interacting with pUL26. Knowledge obtained in this study widens our understanding of HCMV immune evasion and may also provide a new avenue for the use of pUL25-negative strains for vaccine production.
Addresses
  • Institute for Virology, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany.
Autoren
  • Christine Zimmermann
  • Nicole Büscher
  • Steffi Krauter
  • Nadine Krämer
  • Uwe Wolfrum
  • Elisabeth Sehn
  • Stefan Tenzer
  • Bodo Plachter
DOI
10.1128/jvi.01180-18
eISSN
1098-5514
Externe Identifier
  • PubMed Identifier: 30282718
  • PubMed Central ID: PMC6258951
Funding acknowledgements
  • Deutsche Forschungsgemeinschaft: PL236/7-1
  • Else Kröner-Fresenius-Stiftung: 2013_A203
Open access
false
ISSN
0022-538X
Ausgabe der Veröffentlichung
24
Zeitschrift
Journal of virology
Schlüsselwörter
  • Cells, Cultured
  • Fibroblasts
  • Humans
  • Cytomegalovirus
  • Phosphoproteins
  • Ubiquitins
  • Viral Proteins
  • Viral Matrix Proteins
  • Cytokines
  • Proteomics
  • Virus Replication
  • Mutation
  • Immunity, Innate
  • Proteolysis
Sprache
eng
Medium
Electronic-Print
Online publication date
2018
Paginierung
e01180 - e01118
Datum der Veröffentlichung
2018
Status
Published
Datum der Datenerfassung
2018
Titel
The Abundant Tegument Protein pUL25 of Human Cytomegalovirus Prevents Proteasomal Degradation of pUL26 and Supports Its Suppression of ISGylation.
Sub types
  • Research Support, Non-U.S. Gov't
  • research-article
  • Journal Article
Ausgabe der Zeitschrift
92

Files

https://jvi.asm.org/content/jvi/92/24/e01180-18.full.pdf https://europepmc.org/articles/PMC6258951?pdf=render

Data source: Europe PubMed Central

Abstract
The tegument of human cytomegalovirus (HCMV) virions contains proteins that interfere with both the intrinsic and the innate immunity. One protein with a thus far unknown function is pUL25. The deletion of pUL25 in a viral mutant (Towne-ΔUL25) had no impact on the release of virions and subviral dense bodies or on virion morphogenesis. Proteomic analyses showed few alterations in the overall protein composition of extracellular particles. A surprising result, however, was the almost complete absence of pUL26 in virions and dense bodies of Towne-ΔUL25 and a reduction of the large isoform pUL26-p27 in mutant virus-infected cells. pUL26 had been shown to inhibit protein conjugation with the interferon-stimulated gene 15 protein (ISG15), thereby supporting HCMV replication. To test for a functional relationship between pUL25 and pUL26, we addressed the steady-state levels of pUL26 and found them to be reduced in Towne-ΔUL25-infected cells. Coimmunoprecipitation experiments proved an interaction between pUL25 and pUL26. Surprisingly, the overall protein ISGylation was enhanced in Towne-ΔUL25-infected cells, thus mimicking the phenotype of a pUL26-deleted HCMV mutant. The functional relevance of this was confirmed by showing that the replication of Towne-ΔUL25 was more sensitive to beta interferon. The increase of protein ISGylation was also seen in cells infected with a mutant lacking the tegument protein pp65. Upon retesting, we found that pUL26 degradation was also increased when pp65 was unavailable. Our experiments show that both pUL25 and pp65 regulate pUL26 degradation and the pUL26-dependent reduction of ISGylation and add pUL25 as another HCMV tegument protein that interferes with the intrinsic immunity of the host cell.IMPORTANCE Human cytomegalovirus (HCMV) expresses a number of tegument proteins that interfere with the intrinsic and the innate defense mechanisms of the cell. Initial induction of the interferon-stimulated gene 15 protein (ISG15) and conjugation of proteins with ISG15 (ISGylation) by HCMV infection are subsequently attenuated by the expression of the viral IE1, pUL50, and pUL26 proteins. This study adds pUL25 as another factor that contributes to suppression of ISGylation. The tegument protein interacts with pUL26 and prevents its degradation by the proteasome. By doing this, it supports its restrictive influence on ISGylation. In addition, a lack of pUL25 enhances the levels of free ISG15, indicating that the tegument protein may interfere with the interferon response on levels other than interacting with pUL26. Knowledge obtained in this study widens our understanding of HCMV immune evasion and may also provide a new avenue for the use of pUL25-negative strains for vaccine production.
Date of acceptance
2018
Autoren
  • Christine Zimmermann
  • Nicole Büscher
  • Steffi Krauter
  • Nadine Krämer
  • Uwe Wolfrum
  • Elisabeth Sehn
  • Stefan Tenzer
  • Bodo Plachter
Autoren-URL
https://www.ncbi.nlm.nih.gov/pubmed/30282718
DOI
10.1128/JVI.01180-18
eISSN
1098-5514
Externe Identifier
  • PubMed Central ID: PMC6258951
Ausgabe der Veröffentlichung
24
Zeitschrift
J Virol
Schlüsselwörter
  • ISG15
  • ISGylation
  • cytomegalovirus
  • dense bodies
  • pUL25
  • pUL26
  • pp65
  • tegument
  • Cells, Cultured
  • Cytokines
  • Cytomegalovirus
  • Fibroblasts
  • Humans
  • Immunity, Innate
  • Mutation
  • Phosphoproteins
  • Proteolysis
  • Proteomics
  • Ubiquitins
  • Viral Matrix Proteins
  • Viral Proteins
  • Virus Replication
Sprache
eng
Country
United States
PII
JVI.01180-18
Datum der Veröffentlichung
2018
Status
Published online
Datum, an dem der Datensatz öffentlich gemacht wurde
2019
Titel
The Abundant Tegument Protein pUL25 of Human Cytomegalovirus Prevents Proteasomal Degradation of pUL26 and Supports Its Suppression of ISGylation.
Sub types
  • Journal Article
  • Research Support, Non-U.S. Gov't
Ausgabe der Zeitschrift
92

Data source: PubMed

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