Glycosylation-independent ERAD pathway serves as a backup system under ER stress

Mol Biol Cell. 2013 Oct;24(20):3155-63. doi: 10.1091/mbc.E13-03-0138. Epub 2013 Aug 21.


During endoplasmic reticulum (ER)-associated degradation (ERAD), terminally misfolded proteins are retrotranslocated from the ER to the cytosol and degraded by the ubiquitin-proteasome system. Misfolded glycoproteins are recognized by calnexin and transferred to EDEM1, followed by the ER disulfide reductase ERdj5 and the BiP complex. The mechanisms involved in ERAD of nonglycoproteins, however, are poorly understood. Here we show that nonglycoprotein substrates are captured by BiP and then transferred to ERdj5 without going through the calnexin/EDEM1 pathway; after cleavage of disulfide bonds by ERdj5, the nonglycoproteins are transferred to the ERAD scaffold protein SEL1L by the aid of BiP for dislocation into the cytosol. When glucose trimming of the N-glycan groups of the substrates is inhibited, glycoproteins are also targeted to the nonglycoprotein ERAD pathway. These results indicate that two distinct pathways for ERAD of glycoproteins and nonglycoproteins exist in mammalian cells, and these pathways are interchangeable under ER stress conditions.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Calnexin / metabolism
  • Endoplasmic Reticulum / genetics*
  • Endoplasmic Reticulum / metabolism
  • Endoplasmic Reticulum Stress / genetics*
  • Endoplasmic Reticulum Stress / physiology
  • Endoplasmic Reticulum-Associated Degradation / genetics*
  • Endoplasmic Reticulum-Associated Degradation / physiology
  • Glucose / metabolism
  • Glycosylation
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Mice
  • Proteasome Endopeptidase Complex / metabolism
  • Protein Folding
  • Proteolysis
  • Ubiquitin-Protein Ligases / metabolism


  • Edem1 protein, mouse
  • Membrane Proteins
  • Calnexin
  • Ubiquitin-Protein Ligases
  • Proteasome Endopeptidase Complex
  • Glucose