Study on the Physical and Functional Interaction between Fortilin and Peroxiredoxin I
| dc.contributor.advisor | Srivastava, Satish K | |
| dc.contributor.committeeMember | Fujise, Kenichi | |
| dc.contributor.committeeMember | Boehning, Darren F | |
| dc.contributor.committeeMember | Pazdrak, Konrad | |
| dc.contributor.committeeMember | McConnell, Bradley K | |
| dc.creator | Chattopadhyay, Abhijnan | |
| dc.date.accessioned | 2016-05-05T21:35:59Z | |
| dc.date.available | 2016-05-05T21:35:59Z | |
| dc.date.created | 2013-12 | |
| dc.date.submitted | December 2013 | |
| dc.date.updated | 2016-05-05T21:35:59Z | |
| dc.description.abstract | Apoptosis or programmed cell death is a highly regulated cellular process which is essential for the development of an organism as well as for tissue and organ maintenance. Dysregulation of apoptosis is responsible for a variety of disease phenotypes from cancer to neurodegenerative and cardiovascular diseases. Fortilin (FT) is an anti-apoptotic protein that prevents apoptotic cell death under various conditions of cellular stress including UV, chemical and oxidative stress. However, the molecular mechanism of this pro-survival action under conditions of oxidative stress has yet to be elucidated. Using an immunoprecipitation and mass spectrometry-based screening approach, we identified a number of potential fortilin interacting proteins, including the anti-oxidant enzyme peroxiredoxin I (Prx I). Prx I is a thioredoxin-dependent peroxidase enzyme that is known to be protective against reactive oxygen species (ROS)-induced cell death. We confirmed the interaction between FT and Prx I by using various approaches, including reverse co-immunoprecipitation, direct binding and co-localization studies in cultured cells as well as animal tissue and demonstrated that FT stabilizes Prx I in U2OS cells by preventing its proteasomal degradation. Furthermore, our results showed that wild type FT, but not a point mutant of FT that does not bind to Prx I, enhances the enzymatic activity of Prx I. Further investigations revealed that FT inhibits the deactivating phosphorylation of Prx I by the serine/threonine kinase Mst1 in a dose-dependent manner. Additionally, the anti-apoptotic activity of FT under oxidative stress was found to be dependent on its interaction with Prx I. Finally, we demonstrated that a liver-specific knockout of FT exacerbates ethanol-induced oxidative liver damage. Taken together, our data confirm a novel interaction between FT and Prx I that positively regulates the functions of both proteins, leading to increased cytoprotection and may be explored in future as a therapeutic target in oxidative stress-induced pathological conditions. | |
| dc.format.mimetype | application/pdf | |
| dc.identifier.uri | http://hdl.handle.net/2152.3/676 | |
| dc.subject | apoptosis | |
| dc.subject | oxidative stress | |
| dc.subject | fortilin | |
| dc.subject | peroxiredoxin I | |
| dc.subject | enzyme activity | |
| dc.subject | phosphorylation | |
| dc.subject | Mst1 | |
| dc.title | Study on the Physical and Functional Interaction between Fortilin and Peroxiredoxin I | |
| dc.type | Thesis | |
| dc.type.material | text | |
| thesis.degree.department | Biochemistry and Molecular Biology | |
| thesis.degree.discipline | Biochemistry and Molecular Biology | |
| thesis.degree.grantor | The University of Texas Medical Branch at Galveston | |
| thesis.degree.level | Doctoral | |
| thesis.degree.name | Biochemistry and Molecular Biology (Doctoral) |