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β-Arrestin1 and β-Arrestin2 Are Required to Support the Activity of the CXCL12/HMGB1 Heterocomplex on CXCR4

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2020

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D’Agostino, Gianluca
Locati, Massimo
Perez, Laurent
Bianchi, Marco E.
Rüegg, Curzio
Thelen, Marcus
Cecchinato, Valentina
Uguccioni, Mariagrazia
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Frontiers in Immunology. Frontiers Media. 2020, 11, 550824. eISSN 1664-3224. Available under: doi: 10.3389/fimmu.2020.550824

Zusammenfassung

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.

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Fachgebiet (DDC)
570 Biowissenschaften, Biologie

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cell migration, CXCR4, CXCL12, HMGB1, b-arrestin, CXCL12/HMGB1 heterocomplex

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ISO 690D’AGOSTINO, Gianluca, Marc ARTINGER, Massimo LOCATI, Laurent PEREZ, Daniel F. LEGLER, Marco E. BIANCHI, Curzio RÜEGG, Marcus THELEN, Valentina CECCHINATO, Mariagrazia UGUCCIONI, 2020. β-Arrestin1 and β-Arrestin2 Are Required to Support the Activity of the CXCL12/HMGB1 Heterocomplex on CXCR4. In: Frontiers in Immunology. Frontiers Media. 2020, 11, 550824. eISSN 1664-3224. Available under: doi: 10.3389/fimmu.2020.550824
BibTex
@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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