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Proc Natl Acad Sci U S A

Title:		Previously unknown role for the ubiquitin ligase Ubr1 in endoplasmic reticulum-associated protein degradation
Author(s):		Stolz A; Besser S; Hottmann H; Wolf DH;
Address:		"Institut fur Biochemie, Universitat Stuttgart, 70569 Stuttgart, Germany"
Journal Title:		Proc Natl Acad Sci U S A
Year:		2013
Volume:		20130829
Issue:		38
Page Number:		15271 - 15276
DOI:		10.1073/pnas.1304928110
ISSN/ISBN:		1091-6490 (Electronic) 0027-8424 (Print) 0027-8424 (Linking)
Abstract:		"Quality control and degradation of misfolded proteins are essential processes of all cells. The endoplasmic reticulum (ER) is the entry site of proteins into the secretory pathway in which protein folding occurs and terminally misfolded proteins are recognized and retrotranslocated across the ER membrane into the cytosol. Here, proteins undergo polyubiquitination by one of the membrane-embedded ubiquitin ligases, in yeast Hrd1/Der3 (HMG-CoA reductase degradation/degradation of the ER) and Doa10 (degradation of alpha), and are degraded by the proteasome. In this study, we identify cytosolic Ubr1 (E3 ubiquitin ligase, N-recognin) as an additional ubiquitin ligase that can participate in ER-associated protein degradation (ERAD) in yeast. We show that two polytopic ERAD substrates, mutated transporter of the mating type a pheromone, Ste6* (sterile), and cystic fibrosis transmembrane conductance regulator, undergo Ubr1-dependent degradation in the presence and absence of the canonical ER ubiquitin ligases. Whereas in the case of Ste6* Ubr1 is specifically required under stress conditions such as heat or ethanol or in the absence of the canonical ER ligases, efficient degradation of human cystic fibrosis transmembrane conductance regulator requires function of Ubr1 already in wild-type cells under standard growth conditions. Together with the Hsp70 (heat shock protein) chaperone Ssa1 (stress-seventy subfamily A) and the AAA-type ATPase Cdc48 (cell division cycle), Ubr1 directs the substrate to proteasomal degradation. These data unravel another layer of complexity in ERAD"
Keywords:		"Adaptor Proteins, Signal Transducing/metabolism Adenosine Triphosphatases/metabolism Blotting, Western Cell Cycle Proteins/metabolism Cystic Fibrosis Transmembrane Conductance Regulator/*metabolism Electrophoresis, Polyacrylamide Gel Endoplasmic Reticulum;"
Notes:		"MedlineStolz, Alexandra Besser, Stefanie Hottmann, Heike Wolf, Dieter H eng Research Support, Non-U.S. Gov't 2013/08/31 Proc Natl Acad Sci U S A. 2013 Sep 17; 110(38):15271-6. doi: 10.1073/pnas.1304928110. Epub 2013 Aug 29"