Summary of Study ST001334
This data is available at the NIH Common Fund's National Metabolomics Data Repository (NMDR) website, the Metabolomics Workbench, https://www.metabolomicsworkbench.org, where it has been assigned Project ID PR000911. The data can be accessed directly via it's Project DOI: 10.21228/M8XQ28 This work is supported by NIH grant, U2C- DK119886.
See: https://www.metabolomicsworkbench.org/about/howtocite.php
This study contains a large results data set and is not available in the mwTab file. It is only available for download via FTP as data file(s) here.
| Study ID | ST001334 |
| Study Title | Deadly Duality of PEBP1: Shutting off Necroptosis, Turning on Ferroptosis |
| Study Type | Observation study |
| Study Summary | Necroptosis and ferroptosis are two pathways of regulated cell death executed in several major cardiovascular and neurological acute and degenerative diseases. While the necroptosis program relies on activation of RIP1, RIP3 kinases and MLKL, ferroptotic death is triggered by 15- Lipoxygenase (15LO) catalyzed oxidation of arachidonoyl- (AA) or adrenoyl- (AdA) phosphatidylethanolamines (PE) controlled by the phosphatidylethanolamine-binding protein 1 (PEBP1). PEBP1 displays “regulatory” promiscuity towards multiple protein partners, including RAF1 kinase. Given a distinct structural homology between RAF1 kinase and RIP3 kinase, we hypothesized that PEBP1 may interact with RIP3 and act as a switch from necroptosis to ferroptosis. Using computational, genetic and redox lipidomics approaches, we show that PEBP1 liberated from RAF1 kinase binds and sterically inhibits RIP3 thus turning-off necroptosis. Highly expressed 15LO may outcompete and bind PEBP1 to promote AA-PE/AdA-PE oxidation and ferroptosis. Using cell- based and animal models, we identified the conditions disrupting PEBP1’s interactions with RAF1 kinase to alternatively bind/inhibit RIP3 kinase or bind/activate 15LO. We further established that PEBP1 knockdown sensitizes cells to RIP3-mediated necroptosis. These newly established regulatory functions of PEBP1 serve multiple and diverse roles across various human disease states. |
| Institute | University of Pittsburgh |
| Last Name | Anthonymuthu |
| First Name | Tamil |
| Address | 130 desoto street |
| atamil@pitt.edu | |
| Phone | 4123837772 |
| Submit Date | 2020-01-16 |
| Num Groups | 5 |
| Raw Data Available | Yes |
| Raw Data File Type(s) | raw(Thermo) |
| Analysis Type Detail | LC-MS |
| Release Date | 2020-04-16 |
| Release Version | 1 |
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Treatment:
| Treatment ID: | TR001423 |
| Treatment Summary: | Mice were anaesthetized with Nembutal (50 mg/kg) and irradiated to 9.25Gy using a Shepherd Mark 1 Model 68 cesium irradiator at a dose rate of 80 cGy/minute, as described (Huang et al., 2016). |
