Stimulation of an unfolded protein response impairs MHC class I expression.
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.
de Almeida
Sérgio F
SF
Iron Genes and Immune System Laboratory, Instituto de Biologia Molecular e Celular, Universidade do Porto, Rua do Campo Alegre 823, 4150-180 Porto, Portugal.
Fleming
John V
JV
Azevedo
Jorge E
JE
Carmo-Fonseca
Maria
M
de Sousa
Maria
M
D022762:CCAAT-Enhancer-Binding Proteins / Q000276:immunology / Q000378:metabolism; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000276:immunology / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000276:immunology / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000235:genetics / Q000276:immunology; D000071020:Hemochromatosis Protein; D015395:Histocompatibility Antigens Class I / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D006801:Humans; D008562:Membrane Glycoproteins / Q000276:immunology / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D020125:Mutation, Missense; D014176:Protein Biosynthesis / Q000235:genetics / Q000276:immunology; D017510:Protein Folding; D000071701:Regulatory Factor X Transcription Factors; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D014157:Transcription Factors / Q000276:immunology / Q000378:metabolism
D022762:CCAAT-Enhancer-Binding Proteins; D004268:DNA-Binding Proteins; C103673:HFE protein, human; D000071020:Hemochromatosis Protein; D015395:Histocompatibility Antigens Class I; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors; C053387:endoplasmin