Investigating the role of the Caenorhabditis elegans unfolded protein response in immunity and development
Author(s)Richardson, Claire E
Massachusetts Institute of Technology. Dept. of Biology.
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Proteins destined for the secretory pathway are folded, posttranslationally modified, and assembled into complexes in the endoplasmic reticulum (ER). To maintain ER proteostasis, the rate of nascent peptide influx into the ER must be matched with the rate of protein folding and export. An imbalance between peptide influx and ER folding capacity activates a conserved set of signal transduction pathways termed the ER Unfolded Protein Response (UPR), which function to restore ER proteostasis. In metazoans, the UPR is controlled by three signaling pathways, controlled by the ER localized transmembrane sensors IRE-1, PERK/PEK-1, and ATF6/ATF-6. The molecular mechanisms and output of the UPR have been defined largely by exogenously inhibiting ER protein folding, either chemically or through overexpression of unfoldable mutant ER proteins, while genetic studies have implicated essential functions for UPR signaling in normal development and in the pathogenesis of disease. This work defines an essential role for the UPR in Caenorhabditis elegans in protection against host immunity and maintenance of ER proteostasis during development. In Chapter Two, I show that the IRE-1 -XBP- 1 pathway is activated by infection with the bacterial pathogen Pseudomonas aeruginosa and is essential for larval development in the presence of pathogen. Through genetic analyses, I demonstrate that immune activation is necessary and sufficient to activate the IRE-1 -XBP- 1 pathway, and that the function of the IRE-1 -XBP- 1 pathway during infection is to protect against the host immune response. In Chapter Three, I present evidence suggesting that the IRE-1 and PEK- 1 negative feedback loops function constitutively to maintain ER proteostasis, even during growth under standard, "unstressed" conditions. Together, these studies highlight the integral role of UPR signaling in C. elegans physiology, and future work, described in Chapters Four and Five, will use genetic approaches to further define the molecular mechanisms underlying this requirement for UPR activity.
Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Biology, February 2012.Cataloged from PDF version of thesis.Includes bibliographical references.
DepartmentMassachusetts Institute of Technology. Department of Biology
Massachusetts Institute of Technology