TY - JOUR
T1 - Fortilin potentiates the peroxidase activity of Peroxiredoxin-1 and protects against alcohol-induced liver damage in mice
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 - McDougal, Owen M.
AU - Fujise, Ken
N1 - Funding Information:
We thank all members of the Fujise laboratory for their collaborative work. We thank Adriana Paulucci, Ph.D. at the UTMB Optical Microscopy Core Laboratory for her assistance with confocal microscopy. The project was supported in part by grants from the National Heart, Blood, and Lung Institute within the National Institutes of Health (HL68024 and HL117247 to K.F.), American Heart Association Established Investigator Award (0540054N to K.F.), American Heart Association Grant-in-Aid (7770000 to K.F.), March of Dimes Starter Scholar Award (FY12-21 to M.N.K-M.), Canadian Institutes of Health Research (CIHR) and MS Society of Canada grants (to H.F and A.C.P.). During his graduate study, A.C. received the following UTMB intramural awards that were a great encouragement to him and helped him complete the current project: the Jane Welsh Award for Excellence in Cardiovascular Research, the Barbara Bowman Memorial Award for Research Excellence, the Rose and Harry Walk Research Award, and the Biological Chemistry Student Organization Student Award.
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.
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U2 - 10.1038/srep18701
DO - 10.1038/srep18701
M3 - Article
C2 - 26726832
AN - SCOPUS:84952926755
SN - 2045-2322
VL - 6
JO - Scientific reports
JF - Scientific reports
M1 - 18701
ER -