1. Academic Validation
  2. Calnexin mediates the maturation of GPI-anchors through ER retention

Calnexin mediates the maturation of GPI-anchors through ER retention

  • J Biol Chem. 2020 Nov 27;295(48):16393-16410. doi: 10.1074/jbc.RA120.015577.
Xin-Yu Guo 1 Yi-Shi Liu 1 Xiao-Dong Gao 1 Taroh Kinoshita 2 Morihisa Fujita 3
Affiliations

Affiliations

  • 1 Key Laboratory of Carbohydrate Chemistry and Biotechnology, Ministry of Education, School of Biotechnology, Jiangnan University, Wuxi, Jiangsu, China.
  • 2 Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, Japan; WPI Immunology Frontier Research Center, Osaka University, Suita, Osaka, Japan.
  • 3 Key Laboratory of Carbohydrate Chemistry and Biotechnology, Ministry of Education, School of Biotechnology, Jiangnan University, Wuxi, Jiangsu, China. Electronic address: fujita@jiangnan.edu.cn.
Abstract

The protein folding and lipid moiety status of glycosylphosphatidylinositol-anchored proteins (GPI-APs) are monitored in the endoplasmic reticulum (ER), with calnexin playing dual roles in the maturation of GPI-APs. In the present study, we investigated the functions of calnexin in the quality control and lipid remodeling of GPI-APs in the ER. By directly binding the N-glycan on proteins, calnexin was observed to efficiently retain GPI-APs in the ER until they were correctly folded. In addition, sufficient ER retention time was crucial for GPI-inositol deacylation, which is mediated by post-GPI attachment protein 1 (PGAP1). Once the calnexin/calreticulin cycle was disrupted, misfolded and inositol-acylated GPI-APs could not be retained in the ER and were exposed on the plasma membrane. In calnexin/calreticulin-deficient cells, endogenous GPI-anchored Alkaline Phosphatase was expressed on the cell surface, but its activity was significantly decreased. ER stress induced surface expression of misfolded GPI-APs, but proper GPI-inositol deacylation occurred due to the extended time that they were retained in the ER. Our results indicate that calnexin-mediated ER quality control systems for GPI-APs are necessary for both protein folding and GPI-inositol deacylation.

Keywords

ER quality control; Endoplasmic reticulum; endoplasmic reticulum (ER); glycobiology; glycosylphosphatidylinositol; glycosylphosphatidylinositol (GPI anchor); lipid remodeling; protein folding.

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