A time-dependent phase shift in the mammalian unfolded protein response

Dev Cell. 2003 Feb;4(2):265-71. doi: 10.1016/s1534-5807(03)00022-4.

Abstract

Unfolded or misfolded proteins in the endoplasmic reticulum (ER) must be refolded or degraded to maintain homeostasis of the ER. The ATF6 and IRE1-XBP1 pathways are important for the refolding process in mammalian cells; activation of these transcriptional programs culminates in induction of ER-localized molecular chaperones and folding enzymes. We show here that degradation of misfolded glycoprotein substrates requires transcriptional induction of EDEM (ER degradation-enhancing alpha-mannosidase-like protein), and that this is mediated specifically by IRE1-XBP1 and not by ATF6. As XBP1 is produced after ATF6 activation, our results reveal a time-dependent transition in the mammalian unfolded protein response: an ATF6-mediated unidirectional phase (refolding only) is followed by an XBP1-mediated bidirectional phase (refolding plus degradation) as the response progresses.

Publication types

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

MeSH terms

  • Activating Transcription Factor 6
  • Animals
  • Blotting, Western
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Endoplasmic Reticulum / genetics
  • Endoplasmic Reticulum / metabolism*
  • Endoribonucleases
  • Gene Expression Regulation / physiology*
  • Genes, MHC Class II / genetics
  • Glycoproteins / genetics
  • Glycoproteins / metabolism
  • HeLa Cells
  • Humans
  • Immunoblotting
  • Luciferases / metabolism
  • Mannosidases / genetics
  • Mannosidases / metabolism*
  • Membrane Proteins / deficiency
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Mice / embryology*
  • Mice, Knockout
  • Protein Folding
  • Protein-Serine-Threonine Kinases / deficiency
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism*
  • Regulatory Factor X Transcription Factors
  • Signal Transduction
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Transfection
  • X-Box Binding Protein 1

Substances

  • ATF6 protein, human
  • Activating Transcription Factor 6
  • Atf6 protein, mouse
  • DNA-Binding Proteins
  • EDEM1 protein, human
  • Edem1 protein, mouse
  • Glycoproteins
  • Membrane Proteins
  • Regulatory Factor X Transcription Factors
  • Transcription Factors
  • X-Box Binding Protein 1
  • XBP1 protein, human
  • Xbp1 protein, mouse
  • Luciferases
  • ERN2 protein, human
  • Ern2 protein, mouse
  • Protein-Serine-Threonine Kinases
  • Endoribonucleases
  • Mannosidases