Expression of hereditary hemochromatosis C282Y HFE protein in HEK293 cells activates specific endoplasmic reticulum stress responsesReportar como inadecuado




Expression of hereditary hemochromatosis C282Y HFE protein in HEK293 cells activates specific endoplasmic reticulum stress responses - Descarga este documento en PDF. Documentación en PDF para descargar gratis. Disponible también para leer online.

BMC Cell Biology

, 8:30

First Online: 24 July 2007Received: 03 April 2007Accepted: 24 July 2007

Abstract

BackgroundHereditary Hemochromatosis HH is a genetic disease associated with iron overload, in which individuals homozygous for the mutant C282Y HFE associated allele are at risk for the development of a range of disorders particularly liver disease. Conformational diseases are a class of disorders associated with the expression of misfolded protein. HFE C282Y is a mutant protein that does not fold correctly and consequently is retained in the Endoplasmic Reticulum ER. In this context, we sought to identify ER stress signals associated with mutant C282Y HFE protein expression, which may have a role in the molecular pathogenesis of HH.

ResultsVector constructs of Wild type HFE and Mutant C282Y HFE were made and transfected into HEK293 cell lines. We have shown that expression of C282Y HFE protein triggers both an unfolded protein response UPR, as revealed by the increased GRP78, ATF6 and CHOP expression, and an ER overload response EOR, as indicated by NF-κB activation. Furthermore, C282Y HFE protein induced apoptotic responses associated with activation of ER stress. Inhibition studies demonstrated that tauroursodeoxycholic acid, an endogenous bile acid, downregulates these events. Finally, we found that the co-existence of both C282Y HFE and Z alpha 1-antitrypsin protein the protein associated with the liver disease of Z alpha 1-antitrypsin deficiency expression on ER stress responses acted as potential disease modifiers with respect to each other.

ConclusionOur novel observations suggest that both the ER overload response EOR and the unfolded protein response UPR are activated by mutant C282Y HFE protein.

Electronic supplementary materialThe online version of this article doi:10.1186-1471-2121-8-30 contains supplementary material, which is available to authorized users.

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Autor: Matthew W Lawless - Arun K Mankan - Mary White - Michael J O-Dwyer - Suzanne Norris

Fuente: https://link.springer.com/article/10.1186/1471-2121-8-30



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