The endoplasmic reticulum (ER) serves as a warehouse for factors that augment and control the biogenesis of nascent proteins entering the secretory pathway. In turn, this compartment also harbors the machinery that responds to the presence of misfolded proteins by targeting them for proteolysis via a process known as ER-associated degradation (ERAD). During ERAD, substrates are selected, modified with ubiquitin, removed from the ER, and then degraded by the cytoplasmic 26S proteasome. While integral membrane proteins can directly access the ubiquitination machinery that resides in the cytoplasm or on the cytoplasmic face of the ER membrane, soluble ERAD substrates within the lumen must be retrotranslocated from this compartment. In either case, nearly all ERAD substrates are tagged with a polyubiquitin chain, a modification that represents a commitment step to degrade aberrant proteins. However, increasing evidence indicates that the polyubiquitin chain on ERAD substrates can be further modified, serves to recruit ERAD-requiring factors, and may regulate the ERAD machinery. Amino acid side chains other than lysine on ERAD substrates can also be modified with ubiquitin, and post-translational modifications that affect substrate ubiquitination have been observed. Here, we summarize these data and provide an overview of questions driving this field of research.
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February 2017
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Docking simulation predicts that the binding of CD81 extracellular domain-2 (EC2) to the RGD-binding site of integrin alphaVbeta3. CD81 EC2 (in red), integrin alphaV (in light green), and integrin beta3 (in purple). Please see pp. 589–596 for more information. Image provided by Yoshikazu Takada.
Review Article|
February 03 2017
The evolving role of ubiquitin modification in endoplasmic reticulum-associated degradation
G. Michael Preston;
G. Michael Preston
1Department of Cell Biology, University of Pittsburgh, Pittsburgh, PA 15260, U.S.A.
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Jeffrey L. Brodsky
2Department of Biological Sciences, University of Pittsburgh, A320 Langley Hall, Pittsburgh, PA 15260, U.S.A.
Correspondence: Jeffrey L. Brodsky (jbrodsky@pitt.edu)
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Publisher: Portland Press Ltd
Received:
October 31 2016
Revision Received:
December 12 2016
Accepted:
December 14 2016
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© 2017 The Author(s); published by Portland Press Limited on behalf of the Biochemical Society
2017
Biochem J (2017) 474 (4): 445–469.
Article history
Received:
October 31 2016
Revision Received:
December 12 2016
Accepted:
December 14 2016
Citation
G. Michael Preston, Jeffrey L. Brodsky; The evolving role of ubiquitin modification in endoplasmic reticulum-associated degradation. Biochem J 15 February 2017; 474 (4): 445–469. doi: https://doi.org/10.1042/BCJ20160582
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