title: The Mouse Cytomegalovirus Gene m42 Targets Surface Expression of the Protein Tyrosine Phosphatase CD45 in Infected Macrophages.
abstract: The 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.
authors.affiliation: Institute of Virology, Hannover Medical School, Hannover, Germany.
authors.forename: Nadine
authors.initials: N
authors.lastname: Thiel
authors.affiliation: Institute of Virology, Hannover Medical School, Hannover, Germany.
authors.forename: Kirsten A
authors.initials: KA
authors.lastname: Keyser
authors.affiliation: Institute of Virology, University Medical Center of the Johannes Gutenberg University, Mainz, Germany.
authors.forename: Niels A W
authors.identifier: http://orcid.org/0000-0001-9190-6497
authors.initials: NA
authors.lastname: Lemmermann
authors.affiliation: Helmholtz Centre for Infection Research, Braunschweig, Germany.
authors.forename: Jennifer D
authors.initials: JD
authors.lastname: Oduro
authors.affiliation: Institute of Virology, Hannover Medical School, Hannover, Germany.
authors.forename: Karen
authors.initials: K
authors.lastname: Wagner
authors.affiliation: Institute of Virology, Hannover Medical School, Hannover, Germany.
authors.forename: Carina
authors.identifier: http://orcid.org/0000-0001-6590-8413
authors.initials: C
authors.lastname: Elsner
authors.affiliation: Institute of Virology, Medical Center, University of Freiburg, Freiburg, Germany.
authors.forename: Anne
authors.initials: A
authors.lastname: Halenius
authors.affiliation: Department of Histology and Embryology, Faculty of Medicine, University of Rijeka, Rijeka, Croatia.
authors.forename: Tihana
authors.initials: T
authors.lastname: Lenac Roviš
authors.affiliation: Institute of Virology, Hannover Medical School, Hannover, Germany.|Helmholtz Centre for Infection Research, Braunschweig, Germany.
authors.forename: Melanie M
authors.initials: MM
authors.lastname: Brinkmann
authors.affiliation: Department of Histology and Embryology, Faculty of Medicine, University of Rijeka, Rijeka, Croatia.
authors.forename: Stipan
authors.initials: S
authors.lastname: Jonjić
authors.affiliation: Institute of Virology, Hannover Medical School, Hannover, Germany.|Helmholtz Centre for Infection Research, Braunschweig, Germany.
authors.forename: Luka
authors.initials: L
authors.lastname: Cicin-Sain
authors.affiliation: Institute of Virology, Hannover Medical School, Hannover, Germany.
authors.forename: Martin
authors.identifier: http://orcid.org/0000-0002-1227-3933
authors.initials: M
authors.lastname: Messerle
mesh_terms: D000818:Animals; D015536:Down-Regulation; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D015967:Gene Expression Regulation, Viral / Q000235:genetics*; D005814:Genes, Viral / Q000235:genetics*; D057809:HEK293 Cells; D006566:Herpesviridae Infections / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D017493:Leukocyte Common Antigens / Q000096:biosynthesis*; D008264:Macrophages / Q000821:virology*; D051379:Mice; D008807:Mice, Inbred BALB C; D018146:Muromegalovirus; D000067996:RAW 264.7 Cells
chemical_list: D017493:Leukocyte Common Antigens; C516770:Ptprc protein, mouse