title: False start: cotranslational protein ubiquitination and cytosolic protein quality control.
abstract: Maintaining proteostasis is crucial to cells given the toxic potential of misfolded proteins and aggregates. To this end, cells rely on a number of quality control pathways that survey proteins both during, as well as after synthesis to prevent protein aggregation, promote protein folding, and to target terminally misfolded proteins for degradation. In eukaryotes, the ubiquitin proteasome system plays a critical role in protein quality control by selectively targeting proteins for degradation. Recent studies have added to our understanding of cytosolic protein quality control, particularly in the area of cotranslational protein ubiquitination, and suggest that overlap exists across co- and post-translational protein quality control networks. Here, we review recent advances made in the area of cytoplasmic protein quality control with an emphasis on the pathways involved in cotranslational degradation of eukaryotic cytosolic proteins.
  
  
  CONCLUSIONS
  Protein homeostasis, or proteostasis, encompasses the systems required by the cell for the generation and maintenance of the correct levels, conformational state, distribution, and degradation of its proteome. One of the challenges faced by the cell in maintaining proteostasis is the presence of misfolded proteins. Cells therefore have a number of protein quality control pathways to aid in folding or mediate the degradation of misfolded proteins. The ubiquitin proteasome system in particular plays a critical role in protein quality control by selectively targeting proteins for degradation. Nascent polypeptides can be ubiquitinated cotranslationally, however to what extent and how this is used by the cell as a quality control mechanism has, until recently, remained relatively unclear. The picture now emerging is one of two quality control networks: one that recognizes nascent polypeptides on stalled ribosomes and another that targets actively translating polypeptides that misfold, failing to attain their native conformation. These studies underscore the important balance between cotranslational protein folding and degradation in the maintenance of protein homeostasis. In this review we summarize recent advances made in the area of cytoplasmic protein quality control with an emphasis on pathways involved in cotranslational degradation of eukaryotic cytosolic proteins. This article is part of a Special Issue entitled: Can Proteomics Fill the Gap Between Genomics and Phenotypes?
authors: Department of Biochemistry and Molecular Biology, Center for High-Throughput Biology, University of British Columbia, Vancouver, BC V6T 1Z4, Canada.
authors: Sophie A
authors: SA
authors: Comyn
authors: Department of Biochemistry and Molecular Biology, Center for High-Throughput Biology, University of British Columbia, Vancouver, BC V6T 1Z4, Canada.
authors: Gerard T
authors: GT
authors: Chan
authors: Department of Biochemistry and Molecular Biology, Center for High-Throughput Biology, University of British Columbia, Vancouver, BC V6T 1Z4, Canada. Electronic address: mayor@mail.ubc.ca.
authors: Thibault
authors: T
authors: Mayor
mesh_terms: D003600:Cytosol / Q000378:metabolism*; D006706:Homeostasis; D006801:Humans; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D014176:Protein Biosynthesis; D017510:Protein Folding; D011506:Proteins / Q000378:metabolism; D057165:Proteostasis Deficiencies; D011786:Quality Control; D012270:Ribosomes / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D054875:Ubiquitination
chemical_list: D011506:Proteins; D044767:Ubiquitin-Protein Ligases; D046988:Proteasome Endopeptidase Complex
keywords: Protein misfolding; Protein quality control; Proteostasis; Ribosome; Translation; Ubiquitin