Phosphatase Regulation of Mechanical Stress and Aging in C. elegans
| dc.contributor.advisor | Goldsmith, Elizabeth J. | en |
| dc.contributor.committeeMember | Douglas, Peter | en |
| dc.contributor.committeeMember | Mendell, Joshua T. | en |
| dc.contributor.committeeMember | Terman, Jonathan R. | en |
| dc.contributor.committeeMember | Joachimiak, Lukasz | en |
| dc.creator | Egge, Nathan Chandler | en |
| dc.creator.orcid | 0000-0003-4117-9388 | |
| dc.date.accessioned | 2022-09-20T17:15:52Z | |
| dc.date.available | 2022-09-20T17:15:52Z | |
| dc.date.created | 2020-08 | |
| dc.date.issued | 2020-08-01T05:00:00.000Z | |
| dc.date.submitted | August 2020 | |
| dc.date.updated | 2022-09-20T17:15:54Z | |
| dc.description.abstract | Stress and aging embody two related processes driving cellular dysfunction. In either case, environmental stimuli and genetically encoded regulatory mechanisms affect cellular homeostasis and influence adaptation. Phosphatases represent master regulators of stress signaling and modulate cellular responses and fate during stress and aging. Yet, physiologically relevant mechanisms by which these phosphatases are regulated or orchestrate stress response and lifespan are incompletely understood. Herein, I present two scenarios, mechanical trauma and intestinal aging, both of which involve regulation by phosphatases. Mechanical stimuli initiate adaptive signal transduction pathways, but exceeding cell tolerance for physical stress results in degeneration and death via unclear mechanisms. In the nematode C. elegans, I developed a model to study cellular degeneration in response to mechanical stress caused by blunt force trauma. I identified a dual-specificity MAPK phosphatase, VHP-1, as a stress-inducible modulator of neurodegeneration. VHP-1 regulates the transcriptional response to mechanical stress and itself is dually regulated by its target, KGB-1. KGB-1 both activates VHP-1 via a negative feedback loop and represses via inhibition of a deubiquitinase, MATH-33, affecting proteasomal degradation. Thus, I describe an uncharacterized stress response pathway in C. elegans and identify transcriptional and post-translational components comprising a feedback loop on Jun kinase and phosphatase activity. Like stress, aging challenges cell tolerances, instigating death upon inadequacy of homeostatic regulation. Intestinal cells form a vital barrier separating environment from organism. Age impairs intercellular interactions and the cells' capacity to tightly associate within tissues and form an effective barrier necessary for normal systemic function. In particular, the actin cytoskeleton represents a key determinant in maintaining tissue architecture; how age disrupts the actin cytoskeleton, and, in turn, promotes mortality remains unclear. Herein, I show that phosphorylation of ACT-5 compromises C. elegans intestinal barrier integrity and accelerates pathogenesis. Age-related loss of the heat shock transcription factor, HSF-1, disrupts the Jun kinase/Protein Phosphatase I equilibrium, increasing ACT-5 phosphorylation within a troponin-binding site. Phosphorylated ACT-5 accelerates decay of the intestinal terminal web and impairs cell junctions. Therefore, age-associated dysregulation of phosphatase/kinase activity contributes to intestinal dysmorphogenesis and organism death. | en |
| dc.format.mimetype | application/pdf | en |
| dc.identifier.oclc | 1345260475 | |
| dc.identifier.uri | https://hdl.handle.net/2152.5/9964 | |
| dc.language.iso | en | en |
| dc.subject | Aging | en |
| dc.subject | Brain Injuries, Traumatic | en |
| dc.subject | Caenorhabditis elegans | en |
| dc.subject | Caenorhabditis elegans Proteins | en |
| dc.subject | Dual-Specificity Phosphatases | en |
| dc.subject | Nerve Degeneration | en |
| dc.subject | Stress, Mechanical | en |
| dc.title | Phosphatase Regulation of Mechanical Stress and Aging in C. elegans | en |
| dc.type | Thesis | en |
| dc.type.material | text | en |
| thesis.degree.department | Graduate School of Biomedical Sciences | en |
| thesis.degree.discipline | Molecular Biophysics | en |
| thesis.degree.grantor | UT Southwestern Medical Center | en |
| thesis.degree.level | Doctoral | en |
| thesis.degree.name | Doctor of Philosophy | en |