Stimulation of an unfolded protein response impairs MHC class I expression

J Immunol. 2007 Mar 15;178(6):3612-9. doi: 10.4049/jimmunol.178.6.3612.

Abstract

HFE C282Y is an example of a mutant protein that does not fold correctly, is retained in the endoplasmic reticulum, and was found previously to diminish surface expression of MHC class I (MHC-I). We now show that its expression in 293T cells triggers an unfolded protein response (UPR), as revealed by the increased levels of H chain binding protein, GRP94, and C/EBP homologous protein. Elevated levels of these proteins were also found in HFE C282Y homozygous PBMCs. Following the UPR induction, a decrease in MHC-I cell surface expression was observed. This defect in MHC-I could be mimicked, however, by overexpression of transcriptionally active isoforms of activating transcription factor-6 and X box-binding protein-1, which induced the UPR, and reversed in HFE C282Y-expressing cells by using dominant-negative constructs that block UPR signaling. The present results provide evidence to the finding that stimulation of an UPR affects MHC-I expression.

Publication types

  • Clinical Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • CCAAT-Enhancer-Binding Proteins / immunology
  • CCAAT-Enhancer-Binding Proteins / metabolism
  • Cell Line
  • DNA-Binding Proteins / immunology
  • DNA-Binding Proteins / metabolism
  • Endoplasmic Reticulum / immunology
  • Endoplasmic Reticulum / metabolism*
  • Gene Expression Regulation* / genetics
  • Gene Expression Regulation* / immunology
  • Hemochromatosis Protein
  • Histocompatibility Antigens Class I / biosynthesis*
  • Histocompatibility Antigens Class I / genetics
  • Histocompatibility Antigens Class I / immunology
  • Histocompatibility Antigens Class I / metabolism
  • Humans
  • Membrane Glycoproteins / immunology
  • Membrane Glycoproteins / metabolism
  • Membrane Proteins / genetics
  • Membrane Proteins / immunology
  • Membrane Proteins / metabolism*
  • Mutation, Missense
  • Protein Biosynthesis / genetics
  • Protein Biosynthesis / immunology
  • Protein Folding*
  • Regulatory Factor X Transcription Factors
  • Signal Transduction / genetics
  • Signal Transduction / immunology*
  • Transcription Factors / immunology
  • Transcription Factors / metabolism

Substances

  • CCAAT-Enhancer-Binding Proteins
  • DNA-Binding Proteins
  • HFE protein, human
  • Hemochromatosis Protein
  • Histocompatibility Antigens Class I
  • Membrane Glycoproteins
  • Membrane Proteins
  • Regulatory Factor X Transcription Factors
  • Transcription Factors
  • endoplasmin