Organizational diversity among distinct glycoprotein endoplasmic reticulum-associated degradation programs

Mol Biol Cell. 2002 Aug;13(8):2639-50. doi: 10.1091/mbc.e02-02-0068.


Protein folding and quality control in the early secretory pathway function as posttranslational checkpoints in eukaryote gene expression. Herein, an aberrant form of the hepatic secretory protein alpha1-antitrypsin was stably expressed in a human embryonic kidney cell line to elucidate the mechanisms by which glycoprotein endoplasmic reticulum-associated degradation (GERAD) is administered in cells from higher eukaryotes. After biosynthesis, genetic variant PI Z underwent alternative phases of secretion and degradation, the latter of which was mediated by the proteasome. Degradation required release from calnexin- and asparagine-linked oligosaccharide modification by endoplasmic reticulum mannosidase I, the latter of which occurred as PI Z was bound to the molecular chaperone grp78/BiP. That a distinct GERAD program operates in human embryonic kidney cells was supported by the extent of PI Z secretion, apparent lack of polymerization, inability of calnexin to participate in the degradation process, and sequestration of the glycoprotein folding sensor UDP-glucose:glycoprotein glucosyltransferase in the Golgi complex. Because UDP-glucose:glycoprotein glucosyltransferase sustains calnexin binding, its altered distribution is consistent with a GERAD program that hinders the reentry of substrates into the calnexin cycle, allowing grp78/BiP to partner with a lectin, other than calnexin, in the recognition of a two-component GERAD signal to facilitate substrate recruitment. How the processing of a mutant protein, rather than the mutation itself, can contribute to disease pathogenesis, is discussed.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Alkaloids / metabolism
  • Animals
  • Calnexin / metabolism
  • Carbohydrate Sequence
  • Carrier Proteins / metabolism
  • Cell Line
  • Cysteine Endopeptidases / metabolism
  • Endoplasmic Reticulum / metabolism*
  • Endoplasmic Reticulum Chaperone BiP
  • Enzyme Inhibitors / metabolism
  • Glucosyltransferases / metabolism
  • Glycoproteins / metabolism*
  • Heat-Shock Proteins*
  • Humans
  • Molecular Chaperones / metabolism
  • Multienzyme Complexes / metabolism
  • Oligopeptides
  • Proteasome Endopeptidase Complex
  • Protein Folding
  • Protein Isoforms / metabolism
  • Protein Processing, Post-Translational
  • Protein Sorting Signals
  • Protein Transport / physiology*
  • Serine Proteinase Inhibitors / metabolism
  • Uridine Diphosphate Glucose / metabolism
  • alpha 1-Antitrypsin / metabolism*


  • Alkaloids
  • Carrier Proteins
  • Endoplasmic Reticulum Chaperone BiP
  • Enzyme Inhibitors
  • Glycoproteins
  • HSPA5 protein, human
  • Heat-Shock Proteins
  • Molecular Chaperones
  • Multienzyme Complexes
  • Oligopeptides
  • Protein Isoforms
  • Protein Sorting Signals
  • Serine Proteinase Inhibitors
  • alpha 1-Antitrypsin
  • kifunensine
  • lysyl-aspartyl-glutamyl-leucine
  • Calnexin
  • Glucosyltransferases
  • Cysteine Endopeptidases
  • Proteasome Endopeptidase Complex
  • Uridine Diphosphate Glucose