@article{DAgostino2020-09-18Arres-51189,
  year={2020},
  doi={10.3389/fimmu.2020.550824},
  title={β-Arrestin1 and β-Arrestin2 Are Required to Support the Activity of the CXCL12/HMGB1 Heterocomplex on CXCR4},
  volume={11},
  journal={Frontiers in Immunology},
  author={D’Agostino, Gianluca and Artinger, Marc and Locati, Massimo and Perez, Laurent and Legler, Daniel F. and Bianchi, Marco E. and Rüegg, Curzio and Thelen, Marcus and Cecchinato, Valentina and Uguccioni, Mariagrazia},
  note={Article Number: 550824}
}

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    <dc:creator>Cecchinato, Valentina</dc:creator>
    <dc:creator>Uguccioni, Mariagrazia</dc:creator>
    <dc:contributor>D’Agostino, Gianluca</dc:contributor>
    <dc:contributor>Rüegg, Curzio</dc:contributor>
    <dc:date rdf:datatype="http://www.w3.org/2001/XMLSchema#dateTime">2020-10-05T11:38:15Z</dc:date>
    <dcterms:abstract xml:lang="eng">The chemokine receptor CXCR4 plays a fundamental role in homeostasis and pathology by orchestrating recruitment and positioning of immune cells, under the guidance of a CXCL12 gradient. The ability of chemokines to form heterocomplexes, enhancing their function, represents an additional level of regulation on their cognate receptors. In particular, the multi-faceted activity of the heterocomplex formed between CXCL12 and the alarmin HMGB1 is emerging as an unexpected player able to modulate a variety of cell responses, spanning from tissue regeneration to chronic inflammation. Nowadays, little is known on the selective signaling pathways activated when CXCR4 is triggered by the CXCL12/HMGB1 heterocomplex. In the present work, we demonstrate that this heterocomplex acts as a CXCR4 balanced agonist, activating both G protein and β-arrestins-mediated signaling pathways to sustain chemotaxis. We generated β-arrestins knock out HeLa cells by CRISPR/Cas9 technology and show that the CXCL12/HMGB1 heterocomplex-mediated actin polymerization is primarily β-arrestin1 dependent, while chemotaxis requires both β-arrestin1 and β-arrestin2. Triggering of CXCR4 with the CXCL12/HMGB1 heterocomplex leads to an unexpected receptor retention on the cell surface, which depends on β-arrestin2. In conclusion, the CXCL12/HMGB1 heterocomplex engages the β-arrestin proteins differently from CXCL12, promoting a prompt availability of CXCR4 on the cell surface, and enhancing directional cell migration. These data unveil the signaling induced by the CXCL12/HMGB1 heterocomplex in view of identifying biased CXCR4 antagonists or agonists targeting the variety of functions it exerts.</dcterms:abstract>
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    <dc:creator>Locati, Massimo</dc:creator>
    <dc:contributor>Bianchi, Marco E.</dc:contributor>
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    <dc:contributor>Locati, Massimo</dc:contributor>
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    <dc:contributor>Perez, Laurent</dc:contributor>
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    <dc:language>eng</dc:language>
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    <dc:contributor>Legler, Daniel F.</dc:contributor>
    <dcterms:title>β-Arrestin1 and β-Arrestin2 Are Required to Support the Activity of the CXCL12/HMGB1 Heterocomplex on CXCR4</dcterms:title>
    <dc:contributor>Thelen, Marcus</dc:contributor>
    <dc:creator>D’Agostino, Gianluca</dc:creator>
    <dcterms:issued>2020-09-18</dcterms:issued>
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    <dc:creator>Artinger, Marc</dc:creator>
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    <dc:creator>Bianchi, Marco E.</dc:creator>
    <dc:creator>Rüegg, Curzio</dc:creator>
    <dc:contributor>Uguccioni, Mariagrazia</dc:contributor>
    <dc:rights>Attribution 4.0 International</dc:rights>
    <dc:creator>Legler, Daniel F.</dc:creator>
    <dc:creator>Perez, Laurent</dc:creator>
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    <dc:contributor>Artinger, Marc</dc:contributor>
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    <dc:contributor>Cecchinato, Valentina</dc:contributor>
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