title: Fortilin potentiates the peroxidase activity of Peroxiredoxin-1 and protects against alcohol-induced liver damage in mice.
abstract: Fortilin, a pro-survival molecule, inhibits p53-induced apoptosis by binding to the sequence-specific DNA-binding domain of the tumor suppressor protein and preventing it from transcriptionally activating Bax. Intriguingly, fortilin protects cells against ROS-induced cell death, independent of p53. The signaling pathway through which fortilin protects cells against ROS-induced cell death, however, is unknown. Here we report that fortilin physically interacts with the antioxidant enzyme peroxiredoxin-1 (PRX1), protects it from proteasome-mediated degradation, and keeps it enzymatically active by blocking its deactivating phosphorylation by Mst1, a serine/threonine kinase. At the whole animal level, the liver-specific overexpression of fortilin reduced PRX1 phosphorylation in the liver, enhanced PRX1 activity, and protected the transgenic animals against alcohol-induced, ROS-mediated, liver damage. These data suggest the presence of a novel oxidative-stress-handling pathway where the anti-p53 molecule fortilin augments the peroxidase PRX1 by protecting it against degradation and inactivation of the enzyme. Fortilin-PRX1 interaction in the liver could be clinically exploited further to prevent acute alcohol-induced liver damage in humans.
authors.affiliation: Division of Cardiology, Department of Internal Medicine, University of Texas Medical Branch at Galveston, TX 77555, USA.|Department of Biochemistry and Molecular Biology, University of Texas Medical Branch at Galveston, TX 77555, USA.
authors.forename: Abhijnan
authors.initials: A
authors.lastname: Chattopadhyay
authors.affiliation: Division of Cardiology, Department of Internal Medicine, University of Texas Medical Branch at Galveston, TX 77555, USA.
authors.forename: Decha
authors.initials: D
authors.lastname: Pinkaew
authors.affiliation: Division of Cardiology, Department of Internal Medicine, University of Texas Medical Branch at Galveston, TX 77555, USA.
authors.forename: Hung Q
authors.initials: HQ
authors.lastname: Doan
authors.affiliation: Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, NC 27599, USA.
authors.forename: Reed B
authors.initials: RB
authors.lastname: Jacob
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Texas Medical Branch at Galveston, TX 77555, USA.
authors.forename: Sunil K
authors.initials: SK
authors.lastname: Verma
authors.affiliation: McGill University, Montreal, Quebec, Canada.
authors.forename: Hana
authors.initials: H
authors.lastname: Friedman
authors.affiliation: McGill University, Montreal, Quebec, Canada.
authors.forename: Alan C
authors.initials: AC
authors.lastname: Peterson
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Texas Medical Branch at Galveston, TX 77555, USA.|The Institute of Translational Sciences, University of Texas Medical Branch at Galveston, TX 77555, USA.
authors.forename: Muge N
authors.initials: MN
authors.lastname: Kuyumcu-Martinez
authors.affiliation: Department of Chemistry and Biochemistry, Boise State University, 1910 University Drive, Boise, ID 83725-1520, USA.
authors.forename: Owen M
authors.initials: OM
authors.lastname: McDougal
authors.affiliation: Division of Cardiology, Department of Internal Medicine, University of Texas Medical Branch at Galveston, TX 77555, USA.|Department of Biochemistry and Molecular Biology, University of Texas Medical Branch at Galveston, TX 77555, USA.|The Institute of Translational Sciences, University of Texas Medical Branch at Galveston, TX 77555, USA.
authors.forename: Ken
authors.initials: K
authors.lastname: Fujise
mesh_terms: D000438:Alcohols / Q000009:adverse effects*; D000818:Animals; D017209:Apoptosis; D014408:Biomarkers, Tumor / Q000737:chemistry / Q000378:metabolism*; D004195:Disease Models, Animal; D004789:Enzyme Activation; D015870:Gene Expression; D017228:Hepatocyte Growth Factor / Q000378:metabolism; D018398:Homeodomain Proteins / Q000378:metabolism; D008107:Liver Diseases / Q000209:etiology* / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D010084:Oxidation-Reduction; D054464:Peroxiredoxins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011485:Protein Binding; D011487:Protein Conformation; D055503:Protein Multimerization; D059748:Proteolysis; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D000090324:Tumor Protein, Translationally-Controlled 1; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D000438:Alcohols; D014408:Biomarkers, Tumor; D018398:Homeodomain Proteins; D011518:Proto-Oncogene Proteins; C489936:Prrx1 protein, mouse; D017382:Reactive Oxygen Species; D000090324:Tumor Protein, Translationally-Controlled 1; D016159:Tumor Suppressor Protein p53; C082332:macrophage stimulating protein; D017228:Hepatocyte Growth Factor; D054464:Peroxiredoxins; D046988:Proteasome Endopeptidase Complex