Fortilin potentiates the peroxidase activity of Peroxiredoxin-1 and protects against alcohol-induced liver damage in mice

Abhijnan Chattopadhyay, Decha Pinkaew, Hung Q. Doan, Reed B. Jacob, Sunil K. Verma, Hana Friedman, Alan C. Peterson, Neslihan Martinez, Owen M. McDougal, Kenichi Fujise

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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.

Original languageEnglish (US)
Article number18701
JournalScientific Reports
Volume6
DOIs
StatePublished - Jan 4 2016

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Chattopadhyay, A., Pinkaew, D., Doan, H. Q., Jacob, R. B., Verma, S. K., Friedman, H., Peterson, A. C., Martinez, N., McDougal, O. M., & Fujise, K. (2016). Fortilin potentiates the peroxidase activity of Peroxiredoxin-1 and protects against alcohol-induced liver damage in mice. Scientific Reports, 6, [18701]. https://doi.org/10.1038/srep18701