The endocytosis of oxidized LDL via the activation of the angiotensin II type 1 receptor
Toshimasa Takahashi, Yibin Huang, Kōichi Yamamoto, Go Hamano, Akemi Kakino, Fei Kang, Yuki Imaizumi, Hikari Takeshita, Yoichi Nozato, Satoko Nozato, Serina Yokoyama, Motonori Nagasawa, Tatsuo Kawai, Masao Takeda, Taku Fujimoto, Kazuhiro Hongyo, Futoshi Nakagami, Hiroshi Akasaka, Yoichi Takami, Yasushi Takeya, Ken Sugimoto, Herbert Y. Gaisano, Tatsuya Sawamura, Hiromi Rakugi
Abstract
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.