Stimulation of an unfolded protein response impairs MHC class I expression.

Sérgio F de Almeida, John V Fleming, Jorge E Azevedo, Maria Carmo-Fonseca, Maria de Sousa

Journal: Journal of immunology (Baltimore, Md. : 1950) 2007;178(6):3612-9

PMID: 17339458

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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.

Address: Iron Genes and Immune System Laboratory, Instituto de Biologia Molecular e Celular, Universidade do Porto, Rua do Campo Alegre 823, 4150-180 Porto, Portugal.

DOI: 10.4049/jimmunol.178.6.3612

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MeSH Terms: CCAAT-Enhancer-Binding Proteins, Cell Line, DNA-Binding Proteins, Endoplasmic Reticulum, Gene Expression Regulation, Hemochromatosis Protein, Histocompatibility Antigens Class I, Humans, Membrane Glycoproteins, Membrane Proteins, Mutation, Missense, Protein Biosynthesis, Protein Folding, Regulatory Factor X Transcription Factors, Signal Transduction, Transcription Factors