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      HCMV pUL135 Remodels the Actin Cytoskeleton to Impair Immune Recognition of Infected Cells

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          Summary

          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 U L/ b’ domain is associated with loss of virulence. In a screen of U L/ 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.

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          Highlights

          • HCMV UL135 functions during productive infection in order to evade NK and T cells

          • UL135 promotes actin depolymerization and suppresses cytoskeletal remodelling

          • UL135 interacts with ABI1 and ABI2 to relocalize the actin regulatory WAVE2 complex

          • ABI1/2 binding impairs immunological synapse formation to inhibit NK and T cell killing

          Abstract

          Viruses like human cytomegalovirus (HCMV) must evade immune responses in order to establish persistent infection. Stanton et al. identify an HCMV immune evasion strategy whereby the viral protein UL135 modifies the actin cytoskeleton in the infected cell in order to prevent immune cells from forming an immune synapse, thus subverting NK and T cell killing.

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          Most cited references36

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          The WASP-WAVE protein network: connecting the membrane to the cytoskeleton.

          Wiskott-Aldrich syndrome protein (WASP) and WASP-family verprolin-homologous protein (WAVE) family proteins are scaffolds that link upstream signals to the activation of the ARP2/3 complex, leading to a burst of actin polymerization. ARP2/3-complex-mediated actin polymerization is crucial for the reorganization of the actin cytoskeleton at the cell cortex for processes such as cell movement, vesicular trafficking and pathogen infection. Large families of membrane-binding proteins were recently found to interact with WASP and WAVE family proteins, therefore providing a new layer of membrane-dependent regulation of actin polymerization.
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            Formation and function of the lytic NK-cell immunological synapse.

            The natural killer (NK)-cell immunological synapse is the dynamic interface formed between an NK cell and its target cell. Formation of the NK-cell immunological synapse involves several distinct stages, from the initiation of contact with a target cell to the directed delivery of lytic-granule contents for target-cell lysis. Progression through the individual stages is regulated, and this tight regulation underlies the precision with which NK cells select and kill susceptible target cells (including virally infected cells and cancerous cells) that they encounter during their routine surveillance of the body.
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              Surface expression of HLA-E, an inhibitor of natural killer cells, enhanced by human cytomegalovirus gpUL40.

              The nonclassical major histocompatibility complex (MHC) class I molecule HLA-E inhibits natural killer (NK) cell-mediated lysis by interacting with CD94/NKG2A receptors. Surface expression of HLA-E depends on binding of conserved peptides derived from MHC class I molecules. The same peptide is present in the leader sequence of the human cytomegalovirus (HCMV) glycoprotein UL40 (gpUL40). It is shown that, independently of the transporter associated with antigen processing, gpUL40 can up-regulate expression of HLA-E, which protects targets from NK cell lysis. While classical MHC class I molecules are down-regulated, HLA-E is up-regulated by HCMV. Induction of HLA-E surface expression by gpUL40 may represent an escape route for HCMV.
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                Author and article information

                Contributors
                Journal
                Cell Host Microbe
                Cell Host Microbe
                Cell Host & Microbe
                Cell Press
                1931-3128
                1934-6069
                13 August 2014
                13 August 2014
                : 16
                : 2
                : 201-214
                Affiliations
                [1 ]Institute of Infection & Immunity, Cardiff University School of Medicine, Heath Park, Cardiff CF14 4XN, UK
                [2 ]Section of Hepatology, Department of Medicine, Imperial College London, London, W2 1PG, UK
                [3 ]Ludwig-Maximilians-Universität München, Max von Pettenkofer-Institut, Pettenkoferstrasse 9a, 80336 München, Germany
                [4 ]Biological Interfacial Engineering, University of Stuttgart, Nobelstrasse 12, 70569 Stuttgart, Germany
                [5 ]University of Cambridge, Cambridge Institute for Medical Research, Addenbrooke’s Hospital, Hills Road, Cambridge, CB2 0XY, UK
                [6 ]Regional Centre for Applied Molecular Oncology, Masaryk Memorial Cancer Institute, 65653 Brno, Czech Republic
                [7 ]Institute of Cancer and Genetics, Cardiff University School of Medicine, Heath Park, Cardiff CF14 4XN, UK
                [8 ]Medical Research Council, University of Glasgow Centre for Virus Research, Glasgow G11 5JR, UK
                Author notes
                []Corresponding author stantonrj@ 123456cf.ac.uk
                [∗∗ ]Corresponding author wilkinsongw1@ 123456cf.ac.uk
                [9]

                Co-first author

                Article
                S1931-3128(14)00259-5
                10.1016/j.chom.2014.07.005
                4150922
                25121749
                6a92a301-7a6f-4c05-bed1-5dc022ed1d29
                © 2014 The Authors
                History
                : 14 September 2013
                : 10 December 2013
                : 4 July 2014
                Categories
                Article

                Microbiology & Virology
                Microbiology & Virology

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