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

Nadia Martinez-Martin, Abel Viejo-Borbolla, Rocío Martín, Soledad Blanco, Jeffrey L. Benovic, Marcus Thelen and Antonio Alcamí ()
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Nadia Martinez-Martin: Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas—Universidad Autónoma de Madrid
Abel Viejo-Borbolla: Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas—Universidad Autónoma de Madrid
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

Nature Communications, 2015, vol. 6, issue 1, 1-13

Abstract: 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.

Date: 2015
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DOI: 10.1038/ncomms7163

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