Division of Immunology, Transplantation and Infectious Diseases, San Raffaele Scientific Institute, Milan, 20132, Italy.
Department of Chemical Biological Pharmaceutical and Environmental Sciences, University of Messina, Messina, 98166, Italy.
Sci Rep. 2016 Dec 23;6:39382. doi: 10.1038/srep39382.
CCR5 stimulation with natural ligands, such as RANTES, classically induces short-term internalization with transient activation of β-arrestins and rapidly recycling on the cell surface. Here we discovered that, in T cells, natural CCR5 antibodies induce a CCR5-negative phenotype with the involvement of β-arrestin2, which leads to the formation of a stable CCR5 signalosome with both β-arrestin2 and ERK1. The activation of β-arrestin2 is necessary to CCR5 signaling for the signalosome formation and stabilization. When all stimuli were washed out, β-arrestin1 silencing favors the activity of β-arrestin2 for the CCR5 signalosome retention. Interestingly, CCR5 turn from Class A trafficking pattern, normally used for its internalization with natural modulating molecules (i.e. RANTES), into a long lasting Class B type specifically induced by stimulation with natural anti-CCR5 antibodies. This new CCR5 pathway is relevant not only to study in depth the molecular basis of all pathologies where CCR5 is involved but also to generate new antidody-based therapeutics.
CCR5 受其天然配体（如 RANTES）刺激后，通常会导致β-arrestin 的短暂激活和表面快速再循环，从而引起短期内化。在此，我们发现，在 T 细胞中，天然 CCR5 抗体通过β-arrestin2 的参与诱导 CCR5 阴性表型，从而形成具有β-arrestin2 和 ERK1 的稳定 CCR5 信号小体。β-arrestin2 的激活对于信号小体的形成和稳定是 CCR5 信号所必需的。当所有刺激物被洗脱后，β-arrestin1 的沉默有利于β-arrestin2 保留 CCR5 信号小体的活性。有趣的是，CCR5 从正常用于其与天然调节分子（如 RANTES）内化的 A 类转运模式转变为一种新型的 B 类持续模式，这种模式是由天然抗 CCR5 抗体刺激特异性诱导的。这种新的 CCR5 途径不仅与深入研究 CCR5 参与的所有病理学的分子基础有关，而且与基于新抗体的治疗学有关。
