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Herpes simplex virus enhances chemokine function through modulation of receptor trafficking and oligomerization

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  • Nadia Martinez-Martin

    (Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas—Universidad Autónoma de Madrid
    Present address: Department of Protein Chemistry, Genentech Inc., South San Francisco, California 94080, USA)

  • Abel Viejo-Borbolla

    (Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas—Universidad Autónoma de Madrid
    Present address: Institute of Virology, Hannover Medical School, Carl-Neuberg Strasse 1, 30625 Hannover, Germany)

  • Rocío Martín

    (Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas—Universidad Autónoma de Madrid)

  • Soledad Blanco

    (Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas—Universidad Autónoma de Madrid)

  • Jeffrey L. Benovic

    (Kimmel Cancer Center, Thomas Jefferson University)

  • Marcus Thelen

    (Institute for Research in Biomedicine)

  • Antonio Alcamí

    (Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas—Universidad Autónoma de Madrid
    University of Cambridge, Addenbrooke’s Hospital)

Abstract

Glycoprotein G (gG) from herpes simplex virus 1 and 2 (HSV-1 and HSV-2, important human neurotropic pathogens) is the first viral chemokine-binding protein found to potentiate chemokine function. Here we show that gG attaches to cell surface glycosaminoglycans and induces lipid raft clustering, increasing the incorporation of CXCR4 receptors into these microdomains. gG induces conformational rearrangements in CXCR4 homodimers and changes their intracellular partners, leading to sustained, functional chemokine/receptor complexes at the surface. This results in increased chemotaxis dependent on the cholesterol content of the plasma membrane and receptor association to Src-kinases and phosphatidylinositol-3-kinase signalling pathways, but independent of clathrin-mediated endocytosis. Furthermore, using electron microscopy, we show that such enhanced functionality is associated with the accumulation of low-order CXCR4 nanoclusters. Our results provide insights into basic mechanisms of chemokine receptor function and into a viral strategy of immune modulation.

Suggested Citation

  • Nadia Martinez-Martin & Abel Viejo-Borbolla & Rocío Martín & Soledad Blanco & Jeffrey L. Benovic & Marcus Thelen & Antonio Alcamí, 2015. "Herpes simplex virus enhances chemokine function through modulation of receptor trafficking and oligomerization," Nature Communications, Nature, vol. 6(1), pages 1-13, May.
    • Handle: RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms7163
    DOI: 10.1038/ncomms7163
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    Cited by:

    1. Carina Jacobsen & Nina Plückebaum & George Ssebyatika & Sarah Beyer & Lucas Mendes-Monteiro & Jiayi Wang & Kai A. Kropp & Víctor González-Motos & Lars Steinbrück & Birgit Ritter & Claudio Rodríguez-Go, 2024. "Viral modulation of type II interferon increases T cell adhesion and virus spread," Nature Communications, Nature, vol. 15(1), pages 1-18, December.

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