Genotoxic remodeling of the host epithelium

Epithelial barriers, especially that found in the intestine, are highly dynamic, needing to regulate the transport of nutrients and cellular material, while at the same time resisting damage from environmental stresses and preventing pathogen infiltration. Central to maintaining the ability of epithelial cells to appropriately respond to stress and pathogenic bacteria is a cellular degradative process known as autophagy which is responsible for the recycling of intracellular components such as aggregated proteins, damaged organelles, and intracellular pathogens. Here, we report that exposure of epithelial cells to genotoxins, known as cytolethal distending toxins (CDTs), secreted by human mucosal bacterial pathogens impairs formation of specialized vacuoles, autophagosomes, which are required for the sequestration of intracellular components during autophagy. Our studies revealed that CDT treatment of epithelial cells reduced the number of autophagosomes formed in response to potent inducers of autophagy. CDT-mediated impairment of autophagosome formation was dependent on CDT- mediated DNA damage and subsequent DNA damage response. CDT treated cells had diminished levels of cellular LC3-I, a structural protein whose lipidation to LC3-II is necessary for autophagosome formation. Our studies support a yet unrecognized strategy by which some pathogens can interfere with autophagosome formation. In addition to impacting the autophagic process, our studies also identified how genomic instability induced by CDT leads to the reduction of SNAI1, a transcription factor that facilitates intestinal lineage allocation and is critical for epithelial-mesenchymal transitions that occur during human development and metastatic cancers. These studies demonstrate that CDT intoxication leads to cellular changes far beyond simply the often- cited cell cycle arrest and suggests a role for CDTs in disrupting epithelial function through the perturbation of cellular homeostasis.

Name thesis:degree_name

Ph.D.

Level thesis:degree_level

Dissertation

Discipline thesis:degree_discipline

Microbiology

Grantor

University of Illinois at Urbana-Champaign

Year dc:date

2022

Author dc:creator

• Lieu, Dfeau Jia

Contributors dc:contributor

• Blanke, Steven R
• Whitaker, Rachel J
• Wilson, Brenda A
• Olsen, Gary J

• cytolethal distending toxins
• CDT
• autophagy
• SNAI1
• DNA damage response
• genotoxicity

Statement dc:rights

• Copyright 2022 Dfeau Lieu

Language dc:language

en, eng

Handle dc:identifier

https://hdl.handle.net/2142/115585

OAI record oai:identifier

https://www.ideals.illinois.edu/oai-pmh?verb=GetRecord&metadataPrefix=etdms&identifier=oai%3Awww.ideals.illinois.edu%3A2142%2F115585