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J. Biol. Chem., Vol. 282, Issue 38, 27905-27912, September 21, 2007

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Chemical Chaperones Reduce Endoplasmic Reticulum Stress and Prevent Mutant HFE Aggregate Formation^*

Sérgio F. de Almeida¹, Gonçalo Picarote, John V. Fleming, Maria Carmo-Fonseca, Jorge E. Azevedo^¶, and Maria de Sousa²

From the Iron Genes and the Immune System Laboratory, Instituto de Biologia, Molecular e Celular, Universidade do Porto and Instituto de Ciências Biomédicas Abel Salazar, 4150-180 Porto, the Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, 1649-028 Lisboa, and ^¶Organelle Biogenesis and Function, Instituto de Biologia, Molecular e Celular and Instituto de Ciências Biomédicas Abel Salazar, 4150-180 Porto, Portugal

HFE C282Y, the mutant protein associated with hereditary hemochromatosis (HH), fails to acquire the correct conformation in the endoplasmic reticulum (ER) and is targeted for degradation. We have recently shown that an active unfolded protein response (UPR) is present in the cells of patients with HH. Now, by using HEK 293T cells, we demonstrate that the stability of HFE C282Y is influenced by the UPR signaling pathway that promotes its degradation. Treatment of HFE C282Y-expressing cells with tauroursodeoxycholic acid (TUDCA), a bile acid derivative with chaperone properties, or with the chemical chaperone sodium 4-phenylbutyrate (4PBA) impeded the UPR activation. However, although TUDCA led to an increased stability of the mutant protein, 4PBA contributed to a more efficient disposal of HFE C282Y to the degradation route. Fluorescence microscopy and biochemical analysis of the subcellular localization of HFE revealed that a major portion of the C282Y mutant protein forms intracellular aggregates. Although neither TUDCA nor 4PBA restored the correct folding and intracellular trafficking of HFE C282Y, 4PBA prevented its aggregation. These data suggest that TUDCA hampers the UPR activation by acting directly on its signal transduction pathway, whereas 4PBA suppresses ER stress by chemically enhancing the ER capacity to cope with the expression of misfolded HFE, facilitating its degradation. Together, these data shed light on the molecular mechanisms involved in HFE C282Y-related HH and open new perspectives on the use of orally active chemical chaperones as a therapeutic approach for HH.

Received for publication, March 28, 2007 , and in revised form, June 29, 2007.

^* This work was supported in part by grants from Innova/APBRF (to M. d. S.), FCT/Calouste Gulbenkian Foundation (to M. d. S.), and POCI/SAU-MMO/61129/2004 (to J. V. F.). 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Fig. 1.

¹ Recipient of a Ph.D. fellowship funded by the National Foundation for Science and Technology Grant SFRH/BD/11348/2002.

² To whom correspondence should be addressed: Iron Genes and Immune System, Instituto de Biologia, Molecular e Celular, Rua do Campo Alegre 823, 4150-180 Porto, Portugal. Tel.: 351-22-6074956; Fax: 351-22-6098480; E-mail: mdesousa{at}ibmc.up.pt.

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