E3 ubiquitin ligase that recognizes sugar chains.
N-glycosylation of proteins in the endoplasmic reticulum (ER) has a central role in protein quality control. Here we report that N-glycan serves as a signal for degradation by the Skp1-Cullin1-Fbx2-Roc1 (SCF(Fbx2)) ubiquitin ligase complex. The F-box protein Fbx2 (ref. 4) binds specifically to proteins attached to N-linked high-mannose oligosaccharides and subsequently contributes to ubiquitination of N-glycosylated proteins. Pre-integrin beta 1 is a target of Fbx2; these two proteins interact in the cytosol after inhibition of the proteasome. In addition, expression of the mutant Fbx2 Delta F, which lacks the F-box domain that is essential for forming the SCF complex, appreciably blocks degradation of typical substrates of the ER-associated degradation pathway. Our results indicate that SCF(Fbx2) ubiquitinates N-glycosylated proteins that are translocated from the ER to the cytosol by the quality control mechanism.
Department of Tumor Immunology, Tokyo Metropolitan Institute of Medical Science, Bunkyo-ku, Tokyo 113-8613, Japan.
Yukiko
Y
Yoshida
Tomoki
T
Chiba
Fuminori
F
Tokunaga
Hiroshi
H
Kawasaki
Kazuhiro
K
Iwai
Toshiaki
T
Suzuki
Yukishige
Y
Ito
Koji
K
Matsuoka
Minoru
M
Yoshida
Keiji
K
Tanaka
Tadashi
T
Tai
D000818:Animals; D002460:Cell Line; D003546:Cysteine Endopeptidases / Q000378:metabolism; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism; D006023:Glycoproteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D006031:Glycosylation; D006801:Humans; D019012:Integrin beta1 / Q000378:metabolism; D007976:Leupeptins / Q000494:pharmacology; D008025:Ligases / Q000737:chemistry* / Q000378:metabolism*; D046911:Macromolecular Substances; D008358:Mannose / Q000378:metabolism; D051379:Mice; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors / Q000378:metabolism; D011134:Polysaccharides / Q000737:chemistry* / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex; D011485:Protein Binding / Q000187:drug effects; D011498:Protein Precursors / Q000378:metabolism; D012260:Ribonucleases / Q000737:chemistry / Q000378:metabolism; D013379:Substrate Specificity; D014162:Transfection; D025801:Ubiquitin / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases; D000509:alpha-Fetoproteins / Q000737:chemistry / Q000378:metabolism
C505032:CFTR protein, human; D006023:Glycoproteins; D019012:Integrin beta1; D007976:Leupeptins; D046911:Macromolecular Substances; D009097:Multienzyme Complexes; D011134:Polysaccharides; D011498:Protein Precursors; D025801:Ubiquitin; D000509:alpha-Fetoproteins; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D044767:Ubiquitin-Protein Ligases; D012260:Ribonucleases; C029600:ribonuclease B; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex; D008025:Ligases; D008358:Mannose; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde