Stimulation of an Unfolded Protein Response Impairs MHC Class I Expression

• Published in: Journal of Immunology Vol. 178; no. 6; pp. 3612 - 3619
• Main Authors: de Almeida, Sergio F, Fleming, John V, Azevedo, Jorge E, Carmo-Fonseca, Maria, de Sousa, Maria
• Format: Journal Article
• Language: English
• Published: United States Am Assoc Immnol 15.03.2007
• Subjects: 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
• ISSN: 0022-1767; 1550-6606; 1365-2567
• DOI: 10.4049/jimmunol.178.6.3612

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.