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Dennis H. Kim. Tillman, Erik J. (Erik James) Massachusetts Institute of Technology. Department of Biology. Massachusetts Institute of Technology. Department of Biology 2019-01-11T15:06:12Z 2019-01-11T15:06:12Z 2018 2018 http://hdl.handle.net/1721.1/119917 1080866635 Thesis: Ph. D., Massachusetts Institute of Technology, Department of Biology, 2018. This electronic version was submitted by the student author. The certified thesis is available in the Institute Archives and Special Collections. Cataloged from student-submitted PDF version of thesis. Includes bibliographical references. Animals experience intrinsic and extrinsic stressors throughout development and adulthood. To maintain cellular and organismal homeostasis, eukaryota and metazoa rely on conserved, integrated stress response pathways. Throughout its life cycle, the free-living nematode Caenorhabditis elegans encounters diverse microbial taxa, including both nutritional and pathogenic species. Intestinal infection with the pathogenic bacteria Pseudomonas aeruginosa induces a transcriptional innate immune response leading to the secretion of immune effector molecules into the intestinal lumen. Previous work has demonstrated a critical role for the endoplasmic reticulum unfolded protein response in surviving immune activation during larval development. Specifically, the most ancient IRE-1/XBP-1 branch of the UPR is required for larval development during immune activation, whether or not pathogen is present. To understand additional mechanisms regulating ER homeostasis in C. elegans, we conducted a forward genetic screen and identified suppressors of xbp-1 mutant larval lethality on P. aeruginosa. In this work, I outline the characterization of several identified mutations that each affect a gene encoding a broadly conserved transcriptional regulator. A mutation in the gene encoding the forkhead DNA binding domain-containing transcription factor FKH-9 enhances ER homeostasis outside the context of infection and immune activation, but paradoxically sensitizes animals to perturbations in cytosolic proteostasis. My results suggest that loss of fkh-9 enhances translocation of misfolded proteins out of the ER, thereby disrupting cytosolic proteostasis and decreasing proteasomal function. These findings implicate a critical need for balancing proteostasis across cellular compartments during organismal stress, and further investigation of the additional characterized mutants will elucidate the breadth of this phenomenon. by Erik J. Tillman. Ph.D. 134 pages eng Massachusetts Institute of Technology MIT theses are protected by copyright. They may be viewed, downloaded, or printed from this source but further reproduction or distribution in any format is prohibited without written permission. http://dspace.mit.edu/handle/1721.1/7582 Biology. Genetic analysis of endoplasmic reticulum homeostasis during stress and infection of Caenorhabditis elegans Thesis application/pdf false Publication unknown unknown <Publication xmlns="https://www.openaire.eu/cerif-profile/1.1/" id="e56b826a-8e87-4fb8-8f1c-46c2ef4b7fac"> <Type xmlns="https://www.openaire.eu/cerif-profile/vocab/COAR_Publication_Types">http://purl.org/coar/resource_type/c_1843</Type> <Language>eng</Language> <Title>Genetic analysis of endoplasmic reticulum homeostasis during stress and infection of Caenorhabditis elegans</Title> <PublishedIn> <Publication> </Publication> </PublishedIn> <PublicationDate>2018</PublicationDate> <Authors> <Author> <DisplayName>Tillman, Erik J. (Erik James)</DisplayName> <Affiliation> <OrgUnit> </OrgUnit> </Affiliation> </Author> </Authors> <Editors> </Editors> <Publishers> <Publisher> <DisplayName>Massachusetts Institute of Technology</DisplayName> <OrgUnit /> </Publisher> </Publishers> <License>http://dspace.mit.edu/handle/1721.1/7582</License> <Keyword>Biology.</Keyword> <Abstract>Animals experience intrinsic and extrinsic stressors throughout development and adulthood. To maintain cellular and organismal homeostasis, eukaryota and metazoa rely on conserved, integrated stress response pathways. Throughout its life cycle, the free-living nematode Caenorhabditis elegans encounters diverse microbial taxa, including both nutritional and pathogenic species. Intestinal infection with the pathogenic bacteria Pseudomonas aeruginosa induces a transcriptional innate immune response leading to the secretion of immune effector molecules into the intestinal lumen. Previous work has demonstrated a critical role for the endoplasmic reticulum unfolded protein response in surviving immune activation during larval development. Specifically, the most ancient IRE-1/XBP-1 branch of the UPR is required for larval development during immune activation, whether or not pathogen is present. To understand additional mechanisms regulating ER homeostasis in C. elegans, we conducted a forward genetic screen and identified suppressors of xbp-1 mutant larval lethality on P. aeruginosa. In this work, I outline the characterization of several identified mutations that each affect a gene encoding a broadly conserved transcriptional regulator. A mutation in the gene encoding the forkhead DNA binding domain-containing transcription factor FKH-9 enhances ER homeostasis outside the context of infection and immune activation, but paradoxically sensitizes animals to perturbations in cytosolic proteostasis. My results suggest that loss of fkh-9 enhances translocation of misfolded proteins out of the ER, thereby disrupting cytosolic proteostasis and decreasing proteasomal function. These findings implicate a critical need for balancing proteostasis across cellular compartments during organismal stress, and further investigation of the additional characterized mutants will elucidate the breadth of this phenomenon.</Abstract> <Access xmlns="http://purl.org/coar/access_right" > </Access> </Publication>