title: Interplay of substrate retention and export signals in endoplasmic reticulum quality control.
abstract: BACKGROUND
  Endoplasmic reticulum (ER) quality control mechanisms are part of a comprehensive system to manage cell stress. The flux of molecules is monitored to retain folding intermediates and target misfolded molecules to ER-associated degradation (ERAD) pathways. The mechanisms of sorting remain unclear. While some proteins are retained statically, the classical model substrate CPY* is found in COPII transport vesicles, suggesting a retrieval mechanism for retention. However, its management can be even more dynamic. If ERAD is saturated under stress, excess CPY* traffics to the vacuole for degradation. These observations suggest that misfolded proteins might display different signals for their management.
  
  
  RESULTS
  Here, we report the existence of a functional ER exit signal in the pro-domain of CPY*. Compromising its integrity causes ER retention through exclusion from COPII vesicles. The signal co-exists with other signals used for retention and degradation. Physiologically, the export signal is important for stress tolerance. Disabling it converts a benign protein into one that is intrinsically cytotoxic.
  
  
  CONCLUSIONS
  These data reveal the remarkable interplay between opposing signals embedded within ERAD substrate molecules and the mechanisms that decipher them. Our findings demonstrate the diversity of mechanisms deployed for protein quality control and maintenance of protein homeostasis.
authors.affiliation: Temasek Life Sciences Laboratory, Department of Biological Sciences, National University of Singapore, Singapore, Singapore.
authors.forename: Shinichi
authors.initials: S
authors.lastname: Kawaguchi
authors.forename: Chia-Ling
authors.initials: CL
authors.lastname: Hsu
authors.forename: Davis T W
authors.initials: DT
authors.lastname: Ng
mesh_terms: D004721:Endoplasmic Reticulum / Q000378:metabolism*; D006031:Glycosylation; D006056:Golgi Apparatus / Q000378:metabolism; D008856:Microscopy, Fluorescence; D009154:Mutation; D011134:Polysaccharides / Q000378:metabolism; D017510:Protein Folding; D011499:Protein Processing, Post-Translational; D021381:Protein Transport; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D011134:Polysaccharides; D029701:Saccharomyces cerevisiae Proteins