A novel ER alpha-mannosidase-like protein accelerates ER-associated degradation.
The quality control mechanism in the endoplasmic reticulum (ER) discriminates correctly folded proteins from misfolded polypeptides and determines their fate. Terminally misfolded proteins are retrotranslocated from the ER and degraded by cytoplasmic proteasomes, a mechanism known as ER-associated degradation (ERAD). We report the cDNA cloning of Edem, a mouse gene encoding a putative type II ER transmembrane protein. Expression of Edem mRNA was induced by various types of ER stress. Although the luminal region of ER degradation enhancing alpha-mannosidase-like protein (EDEM) is similar to class I alpha1,2-mannosidases involved in N-glycan processing, EDEM did not have enzymatic activity. Overexpression of EDEM in human embryonic kidney 293 cells accelerated the degradation of misfolded alpha1-antitrypsin, and EDEM bound to this misfolded glycoprotein. The results suggest that EDEM is directly involved in ERAD, and targets misfolded glycoproteins for degradation in an N-glycan dependent manner.
Hosokawa
N
N
Department of Molecular and Cellular Biology, Institute for Frontier Medical Sciences, Kyoto University, Kyoto 606-8397, Japan.
Wada
I
I
Hasegawa
K
K
Yorihuzi
T
T
Tremblay
L O
LO
Herscovics
A
A
Nagata
K
K
D000470:Alkaloids / Q000494:pharmacology; D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D003001:Cloning, Molecular; D004721:Endoplasmic Reticulum / Q000737:chemistry / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000235:genetics; D006023:Glycoproteins / Q000378:metabolism*; D006801:Humans; D008361:Mannosidases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008969:Molecular Sequence Data; D017510:Protein Folding; D012313:RNA / Q000235:genetics / Q000378:metabolism; D011817:Rabbits; D016415:Sequence Alignment; D015842:Serine Proteinase Inhibitors / Q000378:metabolism; D014162:Transfection; D000515:alpha 1-Antitrypsin / Q000737:chemistry / Q000378:metabolism*; D043323:alpha-Mannosidase
D000470:Alkaloids; C486654:EDEM1 protein, human; C434526:Edem1 protein, mouse; D004791:Enzyme Inhibitors; D006023:Glycoproteins; D008565:Membrane Proteins; D015842:Serine Proteinase Inhibitors; D000515:alpha 1-Antitrypsin; C065629:kifunensine; D012313:RNA; D008361:Mannosidases; D043323:alpha-Mannosidase