EDEM contributes to maintenance of protein folding efficiency and secretory capacity.
A stringent quality control process selects misfolded polypeptides generated in the endoplasmic reticulum (ER) for ER-associated degradation (ERAD). Here we assessed the maintenance of efficient glycoprotein folding in cells with defective ERAD caused by lack of adaptation of the intralumenal level of ER degradation-enhancing alpha-mannosidase-like protein (EDEM) to an increase in the ER cargo load. When these cells were converted into factories for production of high levels of human beta-secretase, maturation of this N-glycosylated aspartic protease progressed as in wild-type cells initially to gradually become less efficient. Up-regulation of EDEM to strengthen the ERAD machinery (but not up-regulation of calnexin to reinforce the folding machinery) was instrumental in maintaining folding efficiency and secretory capacity. Our data underscore the important role that the degradation machinery plays in maintaining a functional folding environment in the ER.
Institute for Research in Biomedicine, CH-6500 Bellinzona, Switzerland.
Klara K
KK
Eriksson
Riccardo
R
Vago
Verena
V
Calanca
Carmela
C
Galli
Paolo
P
Paganetti
Maurizio
M
Molinari
D000818:Animals; D037281:Calnexin / Q000096:biosynthesis; D002454:Cell Differentiation; D004268:DNA-Binding Proteins / Q000378:metabolism; D003902:Detergents / Q000494:pharmacology; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D005347:Fibroblasts / Q000378:metabolism; D006023:Glycoproteins / Q000737:chemistry; D006031:Glycosylation; D006056:Golgi Apparatus / Q000378:metabolism; D047468:Immunoprecipitation; D007700:Kinetics; D008565:Membrane Proteins / Q000737:chemistry / Q000502:physiology*; D051379:Mice; D009687:Nuclear Proteins / Q000378:metabolism; D011489:Protein Denaturation; D017510:Protein Folding; D000071701:Regulatory Factor X Transcription Factors; D013997:Time Factors; D014157:Transcription Factors; D014162:Transfection; D019076:Transgenes; D015854:Up-Regulation
D004268:DNA-Binding Proteins; D003902:Detergents; C434526:Edem1 protein, mouse; D006023:Glycoproteins; D008565:Membrane Proteins; D009687:Nuclear Proteins; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors; D037281:Calnexin