TY - JOUR
T1 - β-Arrestin1 and β-Arrestin2 Are Required to Support the Activity of the CXCL12/HMGB1 Heterocomplex on CXCR4
T2 - Frontiers in Immunology
AU - D’Agostino, G.
AU - Artinger, M.
AU - Locati, M.
AU - Perez, L.
AU - Legler, D.F.
AU - Bianchi, M.E.
AU - Rüegg, C.
AU - Thelen, M.
AU - Marchese, A.
AU - Rocchi, M.B.L.
AU - Cecchinato, V.
AU - Uguccioni, M.
N1 - Export Date: 11 March 2021
Correspondence Address: Cecchinato, V.; Faculty of Biomedical Sciences, Switzerland; email: valentina.cecchinato@irb.usi.ch
Correspondence Address: Uguccioni, M.; Faculty of Biomedical Sciences, Switzerland; email: mariagrazia.uguccioni@irb.usi.ch
Correspondence Address: Uguccioni, M.; Department of Biomedical Sciences, Italy; email: mariagrazia.uguccioni@irb.usi.ch
Funding details: 280873
Funding details: National Institutes of Health, NIH, GM106727-06A1
Funding details: Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung, SNF, 310030-182727, 310030-189144, 31003A-179248, 3100A0-143718/1
Funding details: Seventh Framework Programme, FP7
Funding details: Helmut Horten Stiftung
Funding text 1: We thank Gabriela Danelon for excellent technical assistance; Dr. David Jarrossay and Diego Morone for assisting in the image analysis. Funding. This work was supported by the European Union?s Programs for research, technological development and demonstration under the grant agreement ADITEC ? 280873 (FP7), the Swiss National Science Foundation (3100A0-143718/1 to MU, 310030-182727 to MT, 31003A-179248 to CR, and 310030-189144 to DL), the Ceschina Foundation, the Helmut Horten Foundation. AM is supported by National Institutes of Health Award GM106727-06A1.
PY - 2020
Y1 - 2020
N2 - 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. © Copyright © 2020 D’Agostino, Artinger, Locati, Perez, Legler, Bianchi, Rüegg, Thelen, Marchese, Rocchi, Cecchinato and Uguccioni.
AB - 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. © Copyright © 2020 D’Agostino, Artinger, Locati, Perez, Legler, Bianchi, Rüegg, Thelen, Marchese, Rocchi, Cecchinato and Uguccioni.
KW - cell migration
KW - CXCL12
KW - CXCL12/HMGB1 heterocomplex
KW - CXCR4
KW - HMGB1
KW - β-arrestin
U2 - 10.3389/fimmu.2020.550824
DO - 10.3389/fimmu.2020.550824
M3 - Article
VL - 11
JO - Front. Immunol.
JF - Front. Immunol.
SN - 1664-3224
ER -