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* Iron Genes and Immune System Laboratory, Instituto de Biologia Molecular e Celular, Universidade do Porto, Porto, Portugal;
Iron Genes and Immune System Laboratory, Instituto de Ciências Biomédicas Abel Salazar, Porto, Portugal;
Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal;
Lysosome and Peroxysome Unit, Instituto de Biologia Molecular e Celular, Universidade do Porto, Porto, Portugal; and
¶ Lysosome and Peroxysome Unit, Instituto de Ciências Biomédicas Abel Salazar, Porto, Portugal
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.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was financed by grants from Innova/American Portuguese Biomedical Research Fund (United States; Principal Investigator: M.d.S.) and Fundação para a Ciência e a Tecnologia/Calouste Gulbenkian Foundation (Portugal; Principal Investigator: M.d.S.), and Grants POCI/SAU-MMO/61129/2004 and SFRH/BPD/14639/2003 (Principal Investigator: J.V.F.). S.F.d.A. is recipient of a PhD fellowship (SFRH/BD/11348/2002) funded by the National Foundation for Science and Technology (Portugal).
2 Address correspondence and reprint requests to Dr. Maria de Sousa, Iron Genes and Immune System, Instituto de Biologia Molecular e Celular, Rua do Campo Alegre 823, 4150-180 Porto, Portugal. E-mail address: mdesousa{at}ibmc.up.pt
3 Abbreviations used in this paper: HH, hereditary hemochromatosis; ATF6, activating transcription factor-6; 
2m, 2-microglobulin; BiP, H chain binding protein; CHOP, C/EBP homologous protein; CT, cytoplasmic tail; ER, endoplasmic reticulum; Ire1, inositol-requiring 1; XBP-1, X box-binding protein-1; sXBP-1, spliced form of XBP-1; TfR1, transferrin receptor 1; UPR, unfolded protein response; wt, wild type; MFI, mean fluorescence intensity; nATF6, nuclear targeted and transcriptionally active fragment of ATF6.
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  S. F. de Almeida, G. Picarote, J. V. Fleming, M. Carmo-Fonseca, J. E. Azevedo, and M. de Sousa Chemical Chaperones Reduce Endoplasmic Reticulum Stress and Prevent Mutant HFE Aggregate Formation J. Biol. Chem., September 21, 2007; 282(38): 27905 - 27912. [Abstract] [Full Text] [PDF]
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