The endocytosis of oxidized LDL via the activation of the angiotensin II type 1 receptor

Toshimasa Takahashi; Yibin Huang; Koichi 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

doi:10.1016/j.isci.2021.102076

The endocytosis of oxidized LDL via the activation of the angiotensin II type 1 receptor

iScience. 2021 Jan 21;24(2):102076. doi: 10.1016/j.isci.2021.102076. eCollection 2021 Feb 19.

Authors

Toshimasa Takahashi^{1

2}, Yibin Huang¹, Koichi Yamamoto¹, Go Hamano¹, Akemi Kakino³, Fei Kang², Yuki Imaizumi¹, Hikari Takeshita¹, Yoichi Nozato¹, Satoko Nozato¹, Serina Yokoyama¹, Motonori Nagasawa¹, Tatsuo Kawai¹, Masao Takeda¹, Taku Fujimoto¹, Kazuhiro Hongyo¹, Futoshi Nakagami¹, Hiroshi Akasaka¹, Yoichi Takami¹, Yasushi Takeya¹, Ken Sugimoto¹, Herbert Y Gaisano², Tatsuya Sawamura³, Hiromi Rakugi¹

Affiliations

¹ Department of Geriatric and General Medicine, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan.
² Department of Medicine, University of Toronto, Toronto, Ontario M5S1A8, Canada.
³ Department of Molecular Pathophysiology, Shinshu University Graduate School of Medicine, Matsumoto, Nagano 390-8621, Japan.

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.

Keywords: Cell Biology; Molecular Biology.