Department of Molecular Life Sciences, University of Zürich, Winterthurerstrasse 190, 8057 Zurich, Switzerland; Cell Biology and Biophysics Unit, European Molecular Biology Laboratory, Meyerhofstraße 1, 69117 Heidelberg, Germany.
Cell Biology and Biophysics Unit, European Molecular Biology Laboratory, Meyerhofstraße 1, 69117 Heidelberg, Germany.
Dev Cell. 2020 Feb 24;52(4):492-508.e10. doi: 10.1016/j.devcel.2020.01.013. Epub 2020 Feb 13.
How tissues migrate robustly through changing guidance landscapes is poorly understood. Here, quantitative imaging is combined with inducible perturbation experiments to investigate the mechanisms that ensure robust tissue migration in vivo. We show that tissues exposed to acute "chemokine floods" halt transiently before they perfectly adapt, i.e., return to the baseline migration behavior in the continued presence of elevated chemokine levels. A chemokine-triggered phosphorylation of the atypical chemokine receptor Cxcr7b reroutes it from constitutive ubiquitination-regulated degradation to plasma membrane recycling, thus coupling scavenging capacity to extracellular chemokine levels. Finally, tissues expressing phosphorylation-deficient Cxcr7b migrate normally in the presence of physiological chemokine levels but show delayed recovery when challenged with elevated chemokine concentrations. This work establishes that adaptation to chemokine fluctuations can be "outsourced" from canonical GPCR signaling to an autonomously acting scavenger receptor that both senses and dynamically buffers chemokine levels to increase the robustness of tissue migration.
组织如何在不断变化的导向景观中稳健地迁移还知之甚少。在这里，定量成像与诱导扰动实验相结合，研究了确保组织在体内稳健迁移的机制。我们发现，暴露于急性“趋化因子洪流”中的组织会短暂停止，然后才会完全适应，即在持续存在升高的趋化因子水平的情况下，恢复到基线迁移行为。趋化因子触发的非典型趋化因子受体 Cxcr7b 的磷酸化将其从组成型泛素化调节的降解重新路由到质膜回收，从而将清除能力与细胞外趋化因子水平偶联起来。最后，表达磷酸化缺陷型 Cxcr7b 的组织在存在生理趋化因子水平的情况下可以正常迁移，但在受到升高的趋化因子浓度挑战时恢复延迟。这项工作确立了对趋化因子波动的适应可以从经典 GPCR 信号转导“外包”到自主作用的清除受体，该受体既能感知又能动态缓冲趋化因子水平，从而提高组织迁移的稳健性。
