Genotoxic remodeling of the host epithelium

Lieu, Dfeau Jia

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

Description

Title

Genotoxic remodeling of the host epithelium

Author(s)

Lieu, Dfeau Jia

Issue Date

2022-04-21

Director of Research (if dissertation) or Advisor (if thesis)

Blanke, Steven R

Doctoral Committee Chair(s)

Blanke, Steven R

Committee Member(s)

• Whitaker, Rachel J
• Wilson, Brenda A
• Olsen, Gary J

Department of Study

Microbiology

Discipline

Microbiology

Degree Granting Institution

University of Illinois at Urbana-Champaign

Degree Name

Ph.D.

Degree Level

Dissertation

Keyword(s)

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

Abstract

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.

Graduation Semester

2022-05

Type of Resource

Thesis

Copyright and License Information

Copyright 2022 Dfeau Lieu

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