title: HCMV pUL135 remodels the actin cytoskeleton to impair immune recognition of infected cells.
abstract: Immune evasion genes help human cytomegalovirus (HCMV) establish lifelong persistence. Without immune pressure, laboratory-adapted HCMV strains have undergone genetic alterations. Among these, the deletion of the UL/b' domain is associated with loss of virulence. In a screen of UL/b', we identified pUL135 as a protein responsible for the characteristic cytopathic effect of clinical HCMV strains that also protected from natural killer (NK) and T cell attack. pUL135 interacted directly with abl interactor 1 (ABI1) and ABI2 to recruit the WAVE2 regulatory complex to the plasma membrane, remodel the actin cytoskeleton and dramatically reduce the efficiency of immune synapse (IS) formation. An intimate association between F-actin filaments in target cells and the IS was dispelled by pUL135 expression. Thus, F-actin in target cells plays a critical role in synaptogenesis, and this can be exploited by pathogens to protect against cytotoxic immune effector cells. An independent interaction between pUL135 and talin disrupted cell contacts with the extracellular matrix.
authors.affiliation: Institute of Infection & Immunity, Cardiff University School of Medicine, Heath Park, Cardiff CF14 4XN, UK. Electronic address: stantonrj@cf.ac.uk.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Stanton
authors.affiliation: Institute of Infection & Immunity, Cardiff University School of Medicine, Heath Park, Cardiff CF14 4XN, UK.
authors.forename: Virginie
authors.initials: V
authors.lastname: Prod'homme
authors.affiliation: Section of Hepatology, Department of Medicine, Imperial College London, London, W2 1PG, UK.
authors.forename: Marco A
authors.initials: MA
authors.lastname: Purbhoo
authors.affiliation: Institute of Infection & Immunity, Cardiff University School of Medicine, Heath Park, Cardiff CF14 4XN, UK.
authors.forename: Melanie
authors.initials: M
authors.lastname: Moore
authors.affiliation: Institute of Infection & Immunity, Cardiff University School of Medicine, Heath Park, Cardiff CF14 4XN, UK.
authors.forename: Rebecca J
authors.initials: RJ
authors.lastname: Aicheler
authors.affiliation: Ludwig-Maximilians-Universität München, Max von Pettenkofer-Institut, Pettenkoferstrasse 9a, 80336 München, Germany.
authors.forename: Marcus
authors.initials: M
authors.lastname: Heinzmann
authors.affiliation: Ludwig-Maximilians-Universität München, Max von Pettenkofer-Institut, Pettenkoferstrasse 9a, 80336 München, Germany; Biological Interfacial Engineering, University of Stuttgart, Nobelstrasse 12, 70569 Stuttgart, Germany.
authors.forename: Susanne M
authors.initials: SM
authors.lastname: Bailer
authors.affiliation: Ludwig-Maximilians-Universität München, Max von Pettenkofer-Institut, Pettenkoferstrasse 9a, 80336 München, Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Haas
authors.affiliation: University of Cambridge, Cambridge Institute for Medical Research, Addenbrooke's Hospital, Hills Road, Cambridge, CB2 0XY, UK.
authors.forename: Robin
authors.initials: R
authors.lastname: Antrobus
authors.affiliation: University of Cambridge, Cambridge Institute for Medical Research, Addenbrooke's Hospital, Hills Road, Cambridge, CB2 0XY, UK.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Weekes
authors.affiliation: University of Cambridge, Cambridge Institute for Medical Research, Addenbrooke's Hospital, Hills Road, Cambridge, CB2 0XY, UK.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Lehner
authors.affiliation: Regional Centre for Applied Molecular Oncology, Masaryk Memorial Cancer Institute, 65653 Brno, Czech Republic.
authors.forename: Borivoj
authors.initials: B
authors.lastname: Vojtesek
authors.affiliation: Institute of Infection & Immunity, Cardiff University School of Medicine, Heath Park, Cardiff CF14 4XN, UK.
authors.forename: Kelly L
authors.initials: KL
authors.lastname: Miners
authors.affiliation: Institute of Cancer and Genetics, Cardiff University School of Medicine, Heath Park, Cardiff CF14 4XN, UK.
authors.forename: Stephen
authors.initials: S
authors.lastname: Man
authors.affiliation: Medical Research Council, University of Glasgow Centre for Virus Research, Glasgow G11 5JR, UK.
authors.forename: Gavin S
authors.initials: GS
authors.lastname: Wilkie
authors.affiliation: Medical Research Council, University of Glasgow Centre for Virus Research, Glasgow G11 5JR, UK.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Davison
authors.affiliation: Institute of Infection & Immunity, Cardiff University School of Medicine, Heath Park, Cardiff CF14 4XN, UK.
authors.forename: Eddie C Y
authors.initials: ECY
authors.lastname: Wang
authors.affiliation: Institute of Infection & Immunity, Cardiff University School of Medicine, Heath Park, Cardiff CF14 4XN, UK.
authors.forename: Peter
authors.initials: P
authors.lastname: Tomasec
authors.affiliation: Institute of Infection & Immunity, Cardiff University School of Medicine, Heath Park, Cardiff CF14 4XN, UK. Electronic address: wilkinsongw1@cf.ac.uk.
authors.forename: Gavin W G
authors.initials: GWG
authors.lastname: Wilkinson
mesh_terms: D008841:Actin Cytoskeleton / Q000378:metabolism*; D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000821:virology; D003587:Cytomegalovirus / Q000276:immunology*; D003598:Cytoskeletal Proteins / Q000378:metabolism; D054884:Host-Pathogen Interactions; D006801:Humans; D054992:Immunological Synapses / Q000821:virology; D056747:Immunomodulation; D007694:Killer Cells, Natural / Q000276:immunology / Q000821:virology; D016608:Talin / Q000378:metabolism; D014764:Viral Proteins / Q000502:physiology*; D051300:Wiskott-Aldrich Syndrome Protein Family / Q000378:metabolism
chemical_list: C513733:ABI1 protein, human; C096831:ABI2 protein, human; D048868:Adaptor Proteins, Signal Transducing; D003598:Cytoskeletal Proteins; D016608:Talin; D014764:Viral Proteins; C120152:WASF2 protein, human; D051300:Wiskott-Aldrich Syndrome Protein Family