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dc.contributor.authorThiel, Nadine
dc.contributor.authorKeyser, Kirsten A
dc.contributor.authorLemmermann, Niels A W
dc.contributor.authorOduro, Jennifer D
dc.contributor.authorWagner, Karen
dc.contributor.authorElsner, Carina
dc.contributor.authorHalenius, Anne
dc.contributor.authorLenac Roviš, Tihana
dc.contributor.authorBrinkmann, Melanie M
dc.contributor.authorJonjić, Stipan
dc.contributor.authorCicin-Sain, Luka
dc.contributor.authorMesserle, Martin
dc.date.accessioned2017-07-20T11:29:58Z
dc.date.available2017-07-20T11:29:58Z
dc.date.issued2016-12
dc.identifier.citationThe Mouse Cytomegalovirus Gene m42 Targets Surface Expression of the Protein Tyrosine Phosphatase CD45 in Infected Macrophages. 2016, 12 (12):e1006057 PLoS Pathog.en
dc.identifier.issn1553-7374
dc.identifier.pmid27926943
dc.identifier.doi10.1371/journal.ppat.1006057
dc.identifier.urihttp://hdl.handle.net/10033/621015
dc.description.abstractThe receptor-like protein tyrosine phosphatase CD45 is expressed on the surface of cells of hematopoietic origin and has a pivotal role for the function of these cells in the immune response. Here we report that following infection of macrophages with mouse cytomegalovirus (MCMV) the cell surface expression of CD45 is drastically diminished. Screening of a set of MCMV deletion mutants allowed us to identify the viral gene m42 of being responsible for CD45 down-modulation. Moreover, expression of m42 independent of viral infection upon retroviral transduction of the RAW264.7 macrophage cell line led to comparable regulation of CD45 expression. In immunocompetent mice infected with an m42 deletion mutant lower viral titers were observed in all tissues examined when compared to wildtype MCMV, indicating an important role of m42 for viral replication in vivo. The m42 gene product was identified as an 18 kDa protein expressed with early kinetics and is predicted to be a tail-anchored membrane protein. Tracking of surface-resident CD45 molecules revealed that m42 induces internalization and degradation of CD45. The observation that the amounts of the E3 ubiquitin ligases Itch and Nedd4 were diminished in cells expressing m42 and that disruption of a PY motif in the N-terminal part of m42 resulted in loss of function, suggest that m42 acts as an activator or adaptor for these Nedd4-like ubiquitin ligases, which mark CD45 for lysosomal degradation. In conclusion, the down-modulation of CD45 expression in MCMV-infected myeloid cells represents a novel pathway of virus-host interaction.
dc.language.isoenen
dc.rights.urihttp://creativecommons.org/licenses/by-nc-sa/4.0/*
dc.subject.meshAnimalsen
dc.subject.meshAntigens, CD45en
dc.subject.meshDown-Regulationen
dc.subject.meshFlow Cytometryen
dc.subject.meshFluorescent Antibody Techniqueen
dc.subject.meshGene Expression Regulation, Viralen
dc.subject.meshGenes, Viralen
dc.subject.meshHEK293 Cellsen
dc.subject.meshHerpesviridae Infectionsen
dc.subject.meshHumansen
dc.subject.meshImmunoblottingen
dc.subject.meshMacrophagesen
dc.subject.meshMiceen
dc.subject.meshMice, Inbred BALB Cen
dc.subject.meshMuromegalovirusen
dc.subject.meshRAW 264.7 Cellsen
dc.titleThe Mouse Cytomegalovirus Gene m42 Targets Surface Expression of the Protein Tyrosine Phosphatase CD45 in Infected Macrophages.en
dc.typeArticleen
dc.contributor.departmentHelmholtz Centre for infection research, Inhoffenstr. 7, 38124 Braunschweig, Germany.en
dc.identifier.journalPLoS pathogensen
refterms.dateFOA2018-06-13T19:46:06Z
html.description.abstractThe receptor-like protein tyrosine phosphatase CD45 is expressed on the surface of cells of hematopoietic origin and has a pivotal role for the function of these cells in the immune response. Here we report that following infection of macrophages with mouse cytomegalovirus (MCMV) the cell surface expression of CD45 is drastically diminished. Screening of a set of MCMV deletion mutants allowed us to identify the viral gene m42 of being responsible for CD45 down-modulation. Moreover, expression of m42 independent of viral infection upon retroviral transduction of the RAW264.7 macrophage cell line led to comparable regulation of CD45 expression. In immunocompetent mice infected with an m42 deletion mutant lower viral titers were observed in all tissues examined when compared to wildtype MCMV, indicating an important role of m42 for viral replication in vivo. The m42 gene product was identified as an 18 kDa protein expressed with early kinetics and is predicted to be a tail-anchored membrane protein. Tracking of surface-resident CD45 molecules revealed that m42 induces internalization and degradation of CD45. The observation that the amounts of the E3 ubiquitin ligases Itch and Nedd4 were diminished in cells expressing m42 and that disruption of a PY motif in the N-terminal part of m42 resulted in loss of function, suggest that m42 acts as an activator or adaptor for these Nedd4-like ubiquitin ligases, which mark CD45 for lysosomal degradation. In conclusion, the down-modulation of CD45 expression in MCMV-infected myeloid cells represents a novel pathway of virus-host interaction.


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