TY - JOUR
T1 - Fortilin Potentiates the Peroxidase Activity of Peroxiredoxin-1 and Protects Against Alcohol-Induced Liver Damage in Mice
AU - McDougal, Owen M.
AU - Chattopadhyay, Abhijnan
AU - Pinkaew, Decha
AU - Doan, Hung Q.
AU - Jacob, Reed B.
AU - Verma, Sunil K.
AU - Friedman, Hana
AU - Peterson, Alan C.
AU - Kuyumcu-Martinez, Muge N.
AU - Fujise, Ken
N1 - McDougal, Owen M. (2016). "Fortilin Potentiates the Peroxidase Activity of Peroxiredoxin-1 and Protects Against Alcohol-Induced Liver Damage in Mice". Scientific Reports, 6,18701-1 - 18701-16. http://dx.doi.org/10.1038/srep18701
PY - 2016/1/4
Y1 - 2016/1/4
N2 - 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.
AB - 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.
KW - apoptosis
KW - hepatitis
KW - molecular biology
KW - oxidoreductases
UR - https://scholarworks.boisestate.edu/chem_facpubs/132
UR - http://www.scopus.com/inward/record.url?scp=84952926755&partnerID=8YFLogxK
U2 - 10.1038/srep18701
DO - 10.1038/srep18701
M3 - Article
C2 - 26726832
VL - 6
JO - Chemistry and Biochemistry Faculty Publications and Presentations
JF - Chemistry and Biochemistry Faculty Publications and Presentations
M1 - 18701
ER -