A role for mammalian Ubc6 homologues in ER-associated protein degradation.
Integral membrane and secretory proteins which fail to fold productively are retained in the endoplasmic reticulum and targeted for degradation by cytoplasmic proteasomes. Genetic and biochemical analyses suggest that substrates of this pathway must be dislocated across the membrane of the endoplasmic reticulum (ER) by a process requiring a functional Sec61 complex and multiubiquitinylation. In yeast, the tail-anchored ubiquitin-conjugating enzyme Ubc6p, which is localized to the cytoplasmic surface of the ER, participates in ER-associated degradation (ERAD) of misfolded proteins. Here we describe the identification of two families of mammalian Ubc6p-related proteins. Members of both families are also located in the ER membrane and display a similar membrane topology as the yeast enzyme. Furthermore we show that expression of elevated levels of wild-type and dominant-negative alleles of these components affects specifically ERAD of the alpha subunit of the T-cell receptor and a mutant form of the CFTR protein. Similarly, we describe that the expression level of Ubc6p in yeast is also critical for ERAD, suggesting that the Ubc6p function is highly conserved from yeast to mammals.
Lenk
Uwe
U
The Max-Delbrück-Centrum für Molekulare Medizin, Robert-Rössle-Str. 10, 13092 Berlin, Germany.
Yu
Helen
H
Walter
Jan
J
Gelman
Marina S
MS
Hartmann
Enno
E
Kopito
Ron R
RR
Sommer
Thomas
T
D000483:Alleles; D000818:Animals; D002478:Cells, Cultured; D003001:Cloning, Molecular; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D005057:Eukaryotic Cells / Q000166:cytology / Q000378:metabolism*; D005656:Fungal Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008025:Ligases / Q000235:genetics / Q000302:isolation & purification* / Q000378:metabolism*; D008322:Mammals / Q000378:metabolism*; D008969:Molecular Sequence Data; D009097:Multienzyme Complexes / Q000378:metabolism*; D010447:Peptide Hydrolases / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex; D017434:Protein Structure, Tertiary / Q000502:physiology; D021381:Protein Transport / Q000502:physiology; D029701:Saccharomyces cerevisiae Proteins; D017386:Sequence Homology, Amino Acid; D012689:Sequence Homology, Nucleic Acid; D025801:Ubiquitin / Q000378:metabolism*; D044763:Ubiquitin-Conjugating Enzymes; D015003:Yeasts / Q000235:genetics / Q000378:metabolism
D005656:Fungal Proteins; D009097:Multienzyme Complexes; D029701:Saccharomyces cerevisiae Proteins; D025801:Ubiquitin; C082461:UBC6 protein, S cerevisiae; C489967:UBE2J1 protein, human; C489966:UBE2J2 protein, human; D044763:Ubiquitin-Conjugating Enzymes; D010447:Peptide Hydrolases; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex; D008025:Ligases