β-Arrestin1 and β-Arrestin2 Are Required to Support the Activity of the CXCL12/HMGB1 Heterocomplex on CXCR4.
β-Arrestin1 and β-Arrestin2 Are Required to Support the Activity of the CXCL12/HMGB1 Heterocomplex on CXCR4.
复制标题
DOI：
10.3389/fimmu.2020.550824
复制
发表时间：
2020
影响因子：
7.3
通讯作者：
Uguccioni M
中科院分区：
文献类型：
--
作者：
D'Agostino G;Artinger M;Locati M;Perez L;Legler DF;Bianchi ME;Rüegg C;Thelen M;Marchese A;Rocchi MBL;Cecchinato V;Uguccioni M
趋化因子受体CXCR 4在CXCL 12梯度的指导下，通过协调免疫细胞的募集和定位，在体内平衡和病理学中起着重要作用。趋化因子形成杂合物的能力，增强其功能，代表了对其同源受体的额外调节水平。特别是，CXCL 12和alarmin HMGB 1之间形成的异源复合物的多方面活性正在成为一种意想不到的参与者，能够调节从组织再生到慢性炎症的各种细胞反应。目前，对CXCL 12/HMGB 1异源复合物触发CXCR 4时激活的选择性信号通路知之甚少。在目前的工作中，我们证明这种杂合物作为CXCR 4平衡激动剂，激活G蛋白和β-抑制蛋白介导的信号通路以维持趋化性。我们通过CRISPR/Cas9技术产生β-arrestins敲除HeLa细胞，并表明CXCL 12/HMGB 1杂合物介导的肌动蛋白聚合主要依赖于β-arrestin 1，而趋化性需要β-arrestin 1和β-arrestin 2。用CXCL 12/HMGB 1异源复合物触发CXCR 4导致细胞表面上意外的受体保留，这取决于β-arrestin 2。总之，CXCL 12/HMGB 1异源复合物与CXCL 12不同地接合β-抑制蛋白，促进细胞表面上CXCR 4的迅速可用性，并增强定向细胞迁移。这些数据揭示了由CXCL 12/HMGB 1异源复合物诱导的信号传导，以鉴定靶向其发挥的各种功能的偏向CXCR 4拮抗剂或激动剂。
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.