Enhancement of endoplasmic reticulum (ER) degradation of misfolded null Hong Kong α1-antitrypsin by human ER mannosidase I

被引:170
作者
Hosokawa, N [1 ]
Tremblay, LO
You, ZP
Herscovics, A
Wada, I
Nagata, K
机构
[1] Kyoto Univ, Dept Mol & Cellular Biol, Inst Frontier Med Sci, Kyoto 6068397, Japan
[2] Japan Sci & Technol Corp, Core Res Evolut Sci & Technol, Saitama 3320012, Japan
[3] McGill Univ, McGill Canc Ctr, Montreal, PQ HEG 1Y6, Canada
[4] Sapporo Med Univ, Dept Biochem, Sapporo, Hokkaido 0608556, Japan
关键词
D O I
10.1074/jbc.M303395200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Misfolded glycoproteins synthesized in the endoplasmic reticulum (ER) are degraded by cytoplasmic proteasomes, a mechanism known as ERAD (ER-associated degradation). In the present study, we demonstrate that ERAD of the misfolded genetic variant-null Hong Kong alpha(1)-antitrypsin is enhanced by overexpression of the ER processing alpha1,2-mannosidase (ER ManI) in HEK 293 cells, indicating the importance of ER ManI in glycoprotein quality control. We showed previously that EDEM, an enzymatically inactive mannosidase homolog, interacts with misfolded alpha1-antitrypsin and accelerates its degradation (Hosokawa, N., Wada, I., Hasegawa, K., Yorihuzi, T., Tremblay, L. O., Herscovics, A., and Nagata, K. (2001) EMBO Rep. 2, 415-422). Herein we demonstrate a combined effect of ER ManI and EDEM on ERAD of misfolded alpha(1)-antitrypsin. We also show that misfolded alpha(1)-antitrypsin NHK contains labeled Glc(1)Man(9)GlcNAc and Man(5-9)GlcNAc released by endo-beta-N-acetylglucosaminidase H in pulse-chase experiments with [2-H-3] mannose. Overexpression of ER ManI greatly increases the formation of Man(8)GlcNAc, induces the formation of Glc(1)Man(8)GlcNAc and increases trimming to Man(5-7)GlcNAc. We propose a model whereby the misfolded glycoprotein interacts with ER ManI and with EDEM, before being recognized by downstream ERAD components. This detailed characterization of oligosaccharides associated with a misfolded glycoprotein raises the possibility that the carbohydrate recognition determinant triggering ERAD may not be restricted to Man(8)GlcNAc(2) isomer B as previous studies have suggested.
引用
收藏
页码:26287 / 26294
页数:8
相关论文
共 27 条
[1]   Ubiquitin and the control of protein fate in the secretory and endocytic pathways [J].
Bonifacino, JS ;
Weissman, AM .
ANNUAL REVIEW OF CELL AND DEVELOPMENTAL BIOLOGY, 1998, 14 :19-57
[2]   Dissecting glycoprotein quality control in the secretory pathway [J].
Cabral, CM ;
Liu, Y ;
Sifers, RN .
TRENDS IN BIOCHEMICAL SCIENCES, 2001, 26 (10) :619-624
[3]  
COX DW, 1995, METABOLIC MOL BASES, P4125
[4]   Setting the standards: Quality control in the secretory pathway [J].
Ellgaard, L ;
Molinari, M ;
Helenius, A .
SCIENCE, 1999, 286 (5446) :1882-1888
[5]   Glycoprotein quality control in the endoplasmic reticulum - Mannose trimming by endoplasmic reticulum mannosidase I times the proteasomal degradation of unassembled immunoglobulin subunits [J].
Fagioli, C ;
Sitia, R .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2001, 276 (16) :12885-12892
[6]   Identification, expression, and characterization of a cDNA encoding human endoplasmic reticulum mannosidase I, the enzyme that catalyzes the first mannose trimming step in mammalian Asn-linked oligosaccharide biosynthesis [J].
Gonzalez, DS ;
Karaveg, K ;
Vandersall-Nairn, AS ;
Lal, A ;
Moremen, KW .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1999, 274 (30) :21375-21386
[7]   Intracellular functions of N-linked glycans [J].
Helenius, A ;
Aebi, M .
SCIENCE, 2001, 291 (5512) :2364-2369
[8]   Importance of glycosidases in mammalian glycoprotein biosynthesis [J].
Herscovics, A .
BIOCHIMICA ET BIOPHYSICA ACTA-GENERAL SUBJECTS, 1999, 1473 (01) :96-107
[9]  
Herscovics A, 2002, GLYCOBIOLOGY, V12, p14G
[10]   A novel ER α‐mannosidase‐like protein accelerates ER‐associated degradation [J].
Nobuko Hosokawa ;
Ikuo Wada ;
Kiyotaka Hasegawa ;
Tetuya Yorihuzi ;
Linda O Tremblay ;
Annette Herscovics ;
Kazuhiro Nagata .
The EMBO Reports, 2001, 2 (5) :415-422