Takahashi Toshimasa, Huang Yibin, Yamamoto Koichi, Hamano Go, Kakino Akemi, Kang Fei, Imaizumi Yuki, Takeshita Hikari, Nozato Yoichi, Nozato Satoko, Yokoyama Serina, Nagasawa Motonori, Kawai Tatsuo, Takeda Masao, Fujimoto Taku, Hongyo Kazuhiro, Nakagami Futoshi, Akasaka Hiroshi, Takami Yoichi, Takeya Yasushi, Sugimoto Ken, Gaisano Herbert Y, Sawamura Tatsuya, Rakugi Hiromi
Department of Geriatric and General Medicine, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan.
Department of Medicine, University of Toronto, Toronto, Ontario M5S1A8, Canada.
iScience. 2021 Jan 21;24(2):102076. doi: 10.1016/j.isci.2021.102076. eCollection 2021 Feb 19.
Arrestin-dependent activation of a G-protein-coupled receptor (GPCR) triggers endocytotic internalization of the receptor complex. We analyzed the interaction between the pattern recognition receptor (PRR) lectin-like oxidized low-density lipoprotein (oxLDL) receptor (LOX-1) and the GPCR angiotensin II type 1 receptor (AT1) to report a hitherto unidentified mechanism whereby internalization of the GPCR mediates cellular endocytosis of the PRR ligand. Using genetically modified Chinese hamster ovary cells, we found that oxLDL activates Gαi but not the Gαq pathway of AT1 in the presence of LOX-1. Endocytosis of the oxLDL-LOX-1 complex through the AT1-β-arrestin pathway was demonstrated by real-time imaging of the membrane dynamics of LOX-1 and visualization of endocytosis of oxLDL. Finally, this endocytotic pathway involving GPCR kinases (GRKs), β-arrestin, and clathrin is relevant in accumulating oxLDL in human vascular endothelial cells. Together, our findings indicate that oxLDL activates selective G proteins and β-arrestin-dependent internalization of AT1, whereby the oxLDL-LOX-1 complex undergoes endocytosis.
视 Arrestin 依赖的 G 蛋白偶联受体（GPCR）激活会触发受体复合物的内吞内化。我们分析了模式识别受体（PRR）凝集素样氧化型低密度脂蛋白（oxLDL）受体（LOX-1）与 GPCR 血管紧张素 II 1 型受体（AT1）之间的相互作用，以报告一种迄今未被识别的机制，即 GPCR 的内化介导了 PRR 配体的细胞内吞作用。使用基因改造的中国仓鼠卵巢细胞，我们发现 oxLDL 在存在 LOX-1 的情况下激活了 AT1 的 Gαi 而非 Gαq 途径。通过对 LOX-1 的膜动力学进行实时成像以及对 oxLDL 的内吞作用进行可视化，证实了 oxLDL-LOX-1 复合物通过 AT1-β-抑制蛋白途径的内吞作用。最后，这种涉及 GPCR 激酶（GRK）、β-抑制蛋白和网格蛋白的内吞途径与 oxLDL 在人血管内皮细胞中的积累有关。总之，我们的研究结果表明，oxLDL 激活选择性 G 蛋白以及 AT1 的 β-抑制蛋白依赖的内化作用，从而使 oxLDL-LOX-1 复合物发生内吞作用。
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