A novel stress-induced EDEM variant regulating endoplasmic reticulum-associated glycoprotein degradation.
Proteins expressed in the endoplasmic reticulum (ER) are subjected to a tight quality control. Persistent association with ER-resident molecular chaperones prevents exit of misfolded or incompletely assembled polypeptides from the ER and forward transport along the secretory line. ER-associated degradation (ERAD) is in place to avoid ER constipation. Folding-incompetent products have to be identified to interrupt futile folding attempts and then targeted for unfolding and dislocation into the cytosol for proteasome-mediated destruction. These processes are better understood for N-glycosylated proteins that represent the majority of polypeptides expressed in the ER. EDEM, a mannosidase-like chaperone, regulates the extraction of misfolded glycoproteins from the calnexin cycle. Here we identify and characterize EDEM2, a novel, stress-regulated mannosidase-like protein that operates in the ER lumen. We show that transcriptional up-regulation of EDEM2 depends on the ER stress-activated transcription factor Xbp1, that EDEM2 up-regulation selectively accelerates ERAD of terminally misfolded glycoproteins by facilitating their extraction from the calnexin cycle, and that the previously characterized homolog EDEM is also a soluble protein of the ER lumen in HEK293 cells.
Olivari
Silvia
S
Institute for Research in Biomedicine, CH-6500 Bellinzona, Switzerland.
Galli
Carmela
C
Alanen
Heli
H
Ruddock
Lloyd
L
Molinari
Maurizio
M
D002460:Cell Line; D004268:DNA-Binding Proteins / Q000378:metabolism; D019992:Databases as Topic; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D006023:Glycoproteins / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism*; D006031:Glycosylation; D006801:Humans; D008361:Mannosidases / Q000737:chemistry; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics; D009687:Nuclear Proteins / Q000378:metabolism; D010455:Peptides / Q000737:chemistry; D011485:Protein Binding; D017510:Protein Folding; D021382:Protein Sorting Signals; D017434:Protein Structure, Tertiary; D000071701:Regulatory Factor X Transcription Factors; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013347:Subcellular Fractions / Q000378:metabolism; D013997:Time Factors; D014157:Transcription Factors; D014158:Transcription, Genetic; D014162:Transfection; D015854:Up-Regulation; D000071717:X-Box Binding Protein 1; D043323:alpha-Mannosidase / Q000737:chemistry* / Q000235:genetics*
D004268:DNA-Binding Proteins; C486654:EDEM1 protein, human; D006023:Glycoproteins; D008565:Membrane Proteins; D009687:Nuclear Proteins; D010455:Peptides; D021382:Protein Sorting Signals; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors; D000071717:X-Box Binding Protein 1; C000605543:XBP1 protein, human; D008361:Mannosidases; C497155:EDEM2 protein, human; D043323:alpha-Mannosidase