Evolutionary conservation and characterization of the metazoan amino acid response
Name
1036985648-MIT.pdf
Description
Full printable version
Size
13.02 MB
Format
Adobe PDF
Checksum (MD5)
9bbbeffe685b33b786f75cad101ed760
Author(s)
Edenius, Maja Lena
Advisor(s)
Malcolm Whitman and Mark Hahn.
Date Issued
2018
Publisher
Massachusetts Institute of Technology
Abstract
Signaling pathways that respond to stress and sense nutrient availability are highly conserved throughout eukaryotes. In mammalian cells, these pathways have evolved to regulate immune responses, representing important therapeutic targets. Interestingly, components of these pathways can be found in plants, yeast and nematodes, where they also participate in response to abiotic and biotic stress. The Amino Acid Response (AAR) pathway, an ancient response to the cellular accumulation of uncharged tRNA, is part of the larger Integrated Stress Response (ISR) in mammals. The ISR consists of multiple branches, each one triggered by distinct stresses that produce phospho-eIF2x signal generation. Each ISR initiating stress results in a unique cellular response due to activation of both the ISR and additional parallel pathway(s) by the initiating stress, but, to date, no such alternate pathway has been identified for the AAR pathway. Despite its integral role in stress adaptation, the ISR has not been studied in early diverging animals. I have identified a highly conserved phosphorylation site in the protein eIF2a, the signature ISR effector, which allowed me to use a mammalian antibody to identify and characterize the ISR in the basal metazoan, Nematostella vectensis, revealing that the core components of the mammalian ISR were present over 550 million years ago in the common ancestor of cnidarians and bilaterians. Additionally, our lab has discovered a novel branch of the AAR pathway that regulates key tissue protective signals. Using evolutionary conservation of this pathway in model organisms, I have identified GCN1 as the branch point that links the signal generation components of the AAR pathway to downstream therapeutic effects. I then used transcriptomic and protein interaction analyses to begin to understand the scope of this pathway and identify key pathway regulators.
Description
Thesis: Ph. D., Joint Program in Oceanography/Applied Ocean Science and Engineering (Massachusetts Institute of Technology, Department of Biology; and the Woods Hole Oceanographic Institution), 2018.
Cataloged from PDF version of thesis.
Includes bibliographical references.
Subjects
Joint Program in Oceanography/Applied Ocean Science and Engineering.
Biology.
Woods Hole Oceanographic Institution.
MIT Department
Joint Program in Oceanography/Applied Ocean Science and Engineering
Woods Hole Oceanographic Institution
Massachusetts Institute of Technology. Department of Biology
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