The evolving role of ubiquitin modification in endoplasmic reticulum-associated degradation.
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.
Department of Cell Biology, University of Pittsburgh, Pittsburgh, PA 15260, U.S.A.
G Michael
GM
Preston
Department of Biological Sciences, University of Pittsburgh, A320 Langley Hall, Pittsburgh, PA 15260, U.S.A. jbrodsky@pitt.edu.
Jeffrey L
JL
Brodsky
D000818:Animals; D004721:Endoplasmic Reticulum / Q000378:metabolism; D060746:Endoplasmic Reticulum-Associated Degradation; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D025821:Polyubiquitin / Q000235:genetics / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D017510:Protein Folding; D011499:Protein Processing, Post-Translational; D059748:Proteolysis; D012441:Saccharomyces cerevisiae / Q000235:genetics* / Q000378:metabolism*; D025801:Ubiquitin / Q000235:genetics / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism; D054875:Ubiquitination
C487709:DERL1 protein, human; D008565:Membrane Proteins; D025801:Ubiquitin; D025821:Polyubiquitin; C482345:SYVN1 protein, human; D044767:Ubiquitin-Protein Ligases; D046988:Proteasome Endopeptidase Complex
molecular chaperone; post-translational modification; proteasome; protein quality control; ubiquitin ligases