Frontiers in Immunology | 卷:11 |
β-Arrestin1 and β-Arrestin2 Are Required to Support the Activity of the CXCL12/HMGB1 Heterocomplex on CXCR4 | |
Mariagrazia Uguccioni1  Marc Artinger2  Adriano Marchese3  Marco B. L. Rocchi4  Massimo Locati5  Curzio Rüegg6  Marco E. Bianchi7  Valentina Cecchinato8  Gianluca D’Agostino8  Marcus Thelen8  Laurent Perez8  Daniel F. Legler10  | |
[1] 0Department of Biomedical Sciences, Humanitas University, Milan, Italy; | |
[2] Biotechnology Institute Thurgau (BITg) at the University of Konstanz, Kreuzlingen, Switzerland; | |
[3] Department of Biochemistry, Medical College of Wisconsin, Milwaukee, WI, United States; | |
[4] Department of Biomolecular Sciences, Biostatistics Unit, University of Urbino, Urbino, Italy; | |
[5] Department of Medical Biotechnologies and Translational Medicine, University of Milan, Milan, Italy; | |
[6] Department of Oncology, Microbiology and Immunology, Faculty of Science and Medicine, University of Fribourg, Fribourg, Switzerland; | |
[7] Division of Genetics and Cell Biology, Vita-Salute San Raffaele University, Milan, Italy; | |
[8] Faculty of Biomedical Sciences, Institute for Research in Biomedicine, Università della Svizzera italiana, Bellinzona, Switzerland; | |
[9] Humanitas Clinical and Research Center IRCCS, Rozzano, Italy; | |
[10] Theodor Kocher Institute, University of Bern, Bern, Switzerland; | |
关键词: cell migration; CXCR4; CXCL12; HMGB1; β-arrestin; CXCL12/HMGB1 heterocomplex; | |
DOI : 10.3389/fimmu.2020.550824 | |
来源: DOAJ |
【 摘 要 】
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.
【 授权许可】
Unknown