Deglycosylation-mediated protein sequence edited NFE2L1 regulates ferroptosis
Abstract/Contents
- Abstract
- Regulated cell death is a fundamental biological phenomenon important for the maintenance of homeostasis and misregulated in disease. Cell death can be executed by several distinct and highly regulated pathways. One nonapoptotic mode of cell death is ferroptosis, an iron-dependent, oxidative form of cell death executed by lipid peroxidation. Here I describe a new method scalable time-lapse analysis of cell death kinetics (STACK) that allows for the continuous measurement of both live and dead cells over a given timeframe, and I develop mathematical models to parameterize cell death over time. Using the STACK approach, I uncovered new ways to understand and quantify cancer cell death and identify an off-target antioxidant effect of the FDA-approved drug bazedoxifene that can potently inhibit ferroptosis. Finally, I apply the STACK approach to uncover a role for the NGLY1/NFE2L1 pathway in the regulation of ferroptosis. Loss of NGLY1 or NFE2L1 promotes ferroptosis in cultured cells. NGLY1-mediated deglycosylation and subsequent protein sequence editing of NFE2L1 is necessary to protect cells against ferroptosis. Mechanistically, I find that sensitivity to ferroptosis upon NGLY1/NFE2L1 disruption is due to loss of the anti-ferroptotic protein GPX4. Genetic overexpression of GPX4 or the NFE2L1 related protein NFE2L2 can compensate for loss of NGLY1 or NFE2L1. Deglycosylation mutant mimic NFE2L18ND acts as a potent inhibitor of ferroptosis that can also compensate for loss of NFE2L2. In my work, I propose that ferroptosis inhibition may serve as a novel therapeutic intervention for the treatment of Ngly1 deficiency, a pathology associated with NGLY1/NFE2L1 dysfunction.
Description
| Type of resource | text |
|---|---|
| Form | electronic resource; remote; computer; online resource |
| Extent | 1 online resource. |
| Place | California |
| Place | [Stanford, California] |
| Publisher | [Stanford University] |
| Copyright date | 2021; ©2021 |
| Publication date | 2021; 2021 |
| Issuance | monographic |
| Language | English |
Creators/Contributors
| Author | Forcina, Giovanni Charles |
|---|---|
| Degree supervisor | Bertozzi, Carolyn R, 1966- |
| Degree supervisor | Dixon, Scott James, 1977- |
| Thesis advisor | Bertozzi, Carolyn R, 1966- |
| Thesis advisor | Dixon, Scott James, 1977- |
| Thesis advisor | Bogyo, Matthew, 1971- |
| Thesis advisor | Cyert, Martha S, 1958- |
| Thesis advisor | Kopito, Ron Rieger |
| Degree committee member | Bogyo, Matthew, 1971- |
| Degree committee member | Cyert, Martha S, 1958- |
| Degree committee member | Kopito, Ron Rieger |
| Associated with | Stanford University, Department of Biology |
Subjects
| Genre | Theses |
|---|---|
| Genre | Text |
Bibliographic information
| Statement of responsibility | Giovanni Charles Forcina. |
|---|---|
| Note | Submitted to the Department of Biology. |
| Thesis | Thesis Ph.D. Stanford University 2021. |
| Location | https://purl.stanford.edu/gd609gc3205 |
Access conditions
- Copyright
- © 2021 by Giovanni Charles Forcina
- License
- This work is licensed under a Creative Commons Attribution Non Commercial 3.0 Unported license (CC BY-NC).
Also listed in
Loading usage metrics...