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Human cytomegalovirus tegument protein pp150 acts as a cyclin A2-CDK-dependent sensor of the host cell cycle and differentiation state.

Upon cell entry, herpesviruses deliver a multitude of premade virion proteins to their hosts. The interplay between these incoming proteins and cell-specific regulatory factors dictates the outcome of infections at the cellular level. Here, we report a unique type of virion--host cell interaction th... Full description

Journal Title: Proceedings of the National Academy of Sciences of the United States of America October 22, 2013, Vol.110(43), pp.17510-17515
Main Author: Bogdanow, Boris
Other Authors: Weisbach, Henry , Von Einem, Jens , Straschewski, Sarah , Voigt, Sebastian , Winkler, Michael , Hagemeier, Christian , Wiebusch, Lüder
Format: Electronic Article Electronic Article
Language: English
Subjects:
ID: E-ISSN: 1091-6490 ; DOI: 10.1073/pnas.1312235110
Link: http://search.proquest.com/docview/1444857928/?pq-origsite=primo
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title: Human cytomegalovirus tegument protein pp150 acts as a cyclin A2-CDK-dependent sensor of the host cell cycle and differentiation state.
format: Article
creator:
  • Bogdanow, Boris
  • Weisbach, Henry
  • Von Einem, Jens
  • Straschewski, Sarah
  • Voigt, Sebastian
  • Winkler, Michael
  • Hagemeier, Christian
  • Wiebusch, Lüder
subjects:
  • Amino Acid Motifs–Genetics
  • Amino Acid Sequence–Genetics
  • Cell Cycle–Metabolism
  • Cell Differentiation–Genetics
  • Cell Line–Metabolism
  • Cell Line, Tumor–Genetics
  • Cyclin A2–Metabolism
  • Cyclin-Dependent Kinases–Physiology
  • Cytomegalovirus–Genetics
  • Flow Cytometry–Genetics
  • Gene Expression Regulation, Viral–Metabolism
  • Genes, Immediate-Early–Genetics
  • Hek293 Cells–Metabolism
  • Host-Pathogen Interactions–Genetics
  • Humans–Metabolism
  • Immunoblotting–Metabolism
  • Luminescent Proteins–Metabolism
  • Microscopy, Fluorescence–Metabolism
  • Mutation–Metabolism
  • Phosphoproteins–Metabolism
  • Phosphorylation–Metabolism
  • Protein Binding–Metabolism
  • Viral Matrix Proteins–Metabolism
  • Cyclin A2
  • Luminescent Proteins
  • Phosphoproteins
  • Viral Matrix Proteins
  • Pp150 Protein, Cytomegalovirus
  • Cyclin-Dependent Kinases
ispartof: Proceedings of the National Academy of Sciences of the United States of America, October 22, 2013, Vol.110(43), pp.17510-17515
description: Upon cell entry, herpesviruses deliver a multitude of premade virion proteins to their hosts. The interplay between these incoming proteins and cell-specific regulatory factors dictates the outcome of infections at the cellular level. Here, we report a unique type of virion--host cell interaction that is essential for the cell cycle and differentiation state-dependent onset of human cytomegalovirus (HCMV) lytic gene expression. The major tegument 150-kDa phosphoprotein (pp150) of HCMV binds to cyclin A2 via a functional RXL/Cy motif resulting in its cyclin A2-dependent phosphorylation. Alanine substitution of the RXL/Cy motif prevents this interaction and allows the virus to fully escape the cyclin-dependent kinase (CDK)-mediated block of immediate early (IE) gene expression in S/G2 phase that normally restricts the onset of the HCMV replication cycle to G0/G1. Furthermore, the cyclin A2--CDK-pp150 axis is also involved in the establishment of HCMV quiescence in NTera2 cells, showing the importance of this molecular switch for differentiation state-dependent regulation of IE gene expression. Consistent with the known nucleocapsid-binding function of pp150, its RXL/Cy-dependent phosphorylation affects gene expression of the parental virion only, suggesting a cis-acting, virus particle-associated mechanism of control. The pp150 homologs of other primate and mammalian CMVs lack an RXL/Cy motif and accordingly even the nearest relative of HCMV, chimpanzee CMV, starts its lyric cycle in a cell cycle-independent manner. Thus, HCMV has evolved a molecular sensor for cyclin A2-CDK activity to restrict its IE gene expression program as a unique level of self-limitation and adaptation to its human host. www.pnas.org/cgi/doi/10.1073/pnas.1312235110
language: eng
source:
identifier: E-ISSN: 1091-6490 ; DOI: 10.1073/pnas.1312235110
fulltext: fulltext
issn:
  • 10916490
  • 1091-6490
url: Link


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titleHuman cytomegalovirus tegument protein pp150 acts as a cyclin A2-CDK-dependent sensor of the host cell cycle and differentiation state.
creatorBogdanow, Boris ; Weisbach, Henry ; Von Einem, Jens ; Straschewski, Sarah ; Voigt, Sebastian ; Winkler, Michael ; Hagemeier, Christian ; Wiebusch, Lüder
contributorBogdanow, Boris (correspondence author) ; Bogdanow, Boris (record owner)
ispartofProceedings of the National Academy of Sciences of the United States of America, October 22, 2013, Vol.110(43), pp.17510-17515
identifierE-ISSN: 1091-6490 ; DOI: 10.1073/pnas.1312235110
subjectAmino Acid Motifs–Genetics ; Amino Acid Sequence–Genetics ; Cell Cycle–Metabolism ; Cell Differentiation–Genetics ; Cell Line–Metabolism ; Cell Line, Tumor–Genetics ; Cyclin A2–Metabolism ; Cyclin-Dependent Kinases–Physiology ; Cytomegalovirus–Genetics ; Flow Cytometry–Genetics ; Gene Expression Regulation, Viral–Metabolism ; Genes, Immediate-Early–Genetics ; Hek293 Cells–Metabolism ; Host-Pathogen Interactions–Genetics ; Humans–Metabolism ; Immunoblotting–Metabolism ; Luminescent Proteins–Metabolism ; Microscopy, Fluorescence–Metabolism ; Mutation–Metabolism ; Phosphoproteins–Metabolism ; Phosphorylation–Metabolism ; Protein Binding–Metabolism ; Viral Matrix Proteins–Metabolism ; Cyclin A2 ; Luminescent Proteins ; Phosphoproteins ; Viral Matrix Proteins ; Pp150 Protein, Cytomegalovirus ; Cyclin-Dependent Kinases
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descriptionUpon cell entry, herpesviruses deliver a multitude of premade virion proteins to their hosts. The interplay between these incoming proteins and cell-specific regulatory factors dictates the outcome of infections at the cellular level. Here, we report a unique type of virion--host cell interaction that is essential for the cell cycle and differentiation state-dependent onset of human cytomegalovirus (HCMV) lytic gene expression. The major tegument 150-kDa phosphoprotein (pp150) of HCMV binds to cyclin A2 via a functional RXL/Cy motif resulting in its cyclin A2-dependent phosphorylation. Alanine substitution of the RXL/Cy motif prevents this interaction and allows the virus to fully escape the cyclin-dependent kinase (CDK)-mediated block of immediate early (IE) gene expression in S/G2 phase that normally restricts the onset of the HCMV replication cycle to G0/G1. Furthermore, the cyclin A2--CDK-pp150 axis is also involved in the establishment of HCMV quiescence in NTera2 cells, showing the importance of this molecular switch for differentiation state-dependent regulation of IE gene expression. Consistent with the known nucleocapsid-binding function of pp150, its RXL/Cy-dependent phosphorylation affects gene expression of the parental virion only, suggesting a cis-acting, virus particle-associated mechanism of control. The pp150 homologs of other primate and mammalian CMVs lack an RXL/Cy motif and accordingly even the nearest relative of HCMV, chimpanzee CMV, starts its lyric cycle in a cell cycle-independent manner. Thus, HCMV has evolved a molecular sensor for cyclin A2-CDK activity to restrict its IE gene expression program as a unique level of self-limitation and adaptation to its human host. www.pnas.org/cgi/doi/10.1073/pnas.1312235110
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titleHuman cytomegalovirus tegument protein pp150 acts as a cyclin A2-CDK-dependent sensor of the host cell cycle and differentiation state.
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