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

Frontiers in Immunology

卷:11

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