title: Involvement of endoplasmic reticulum stress in hereditary tyrosinemia type I.
abstract: Hereditary tyrosinemia type I (HTI) is the most severe disease of the tyrosine degradation pathway. HTI is caused by a deficiency of fumarylacetoacetate hydrolase (FAH), the enzyme responsible for the hydrolysis of fumarylacetoacetate (FAA). As a result, there is an accumulation of metabolites such as maleylacetoacetate, succinylacetone, and FAA. The latter was shown to display mutagenic, cytostatic, and apoptogenic activities and to cause chromosomal instability. Herein, we demonstrate that FAA also causes a cellular insult leading to the endoplasmic reticulum (ER) stress signaling. Treatment of V79 Chinese hamster lung cells with an apoptogenic dose of FAA (100 mum) causes an early induction of the ER resident chaperone GRP78/BiP and a simultaneous phosphorylation of the eIF2alpha. FAA treatment also causes a subsequent induction of the proapoptotic CHOP (CEBP homologous protein) transcription factor as well as a late activation of caspase-12. Data obtained from fah(-/-) mice taken off the therapeutic 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3 cyclohexanedione drug are similar. However, in this mouse model, there is also an increase in proteasome activity indicative of ER-associated degradation. This difference observed between the two models may be due to the fact that the murine model measures the effects of all metabolites accumulating in hereditary tyrosinemia type I as opposed to the cellular model that only measures the effects of exogenous FAA.
authors.affiliation: Laboratory of Cell and Developmental Genetics, Department of Medicine, Centre de Recherche sur la Fonction, la Structure, et l'Ingénierie des Protéines, Pavillon Marchand, Université Laval, Ste-Foy, Québec G1K 7P4, Canada.
authors.forename: Anne
authors.initials: A
authors.lastname: Bergeron
authors.forename: Rossana
authors.initials: R
authors.lastname: Jorquera
authors.forename: Diana
authors.initials: D
authors.lastname: Orejuela
authors.forename: Robert M
authors.initials: RM
authors.lastname: Tanguay
mesh_terms: D000090:Acetoacetates / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D006224:Cricetinae; D003512:Cyclohexanones / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D000091342:Endoplasmic Reticulum Chaperone BiP; D004791:Enzyme Inhibitors / Q000378:metabolism; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism; D006360:Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D006867:Hydrolases / Q000235:genetics / Q000378:metabolism; D008099:Liver / Q000737:chemistry / Q000378:metabolism; D008168:Lung / Q000166:cytology; D051379:Mice; D018345:Mice, Knockout; D018832:Molecular Chaperones / Q000378:metabolism; D009579:Nitrobenzoates / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D014158:Transcription, Genetic; D020176:Tyrosinemias / Q000378:metabolism*
chemical_list: D000090:Acetoacetates; D003512:Cyclohexanones; D000091342:Endoplasmic Reticulum Chaperone BiP; D004791:Enzyme Inhibitors; D015852:Eukaryotic Initiation Factor-2; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins; C000717248:Hspa5 protein, mouse; D018832:Molecular Chaperones; D009579:Nitrobenzoates; C105171:fumarylacetoacetate; D006867:Hydrolases; D046988:Proteasome Endopeptidase Complex; C020156:fumarylacetoacetase; C077073:nitisinone