Dissertation
IRF6 regulates the recycling of E-cadherin at the cell membrane
University of Iowa
Doctor of Philosophy (PhD), University of Iowa
Spring 2023
DOI: 10.25820/etd.007179
Abstract
Cellular adhesions are essential structures mediating tissue integrity as well as numerous cellular processes, including migration and stratification. Consequently, any disruption in the dynamic of these protein complexes lead to severe defects. Therefore, understanding the molecular regulation of cellular adhesions is imperative. Interferon regulatory factor 6 (IRF6) is a master regulator of epidermal migration and differentiation, yet how it affects cellular adhesions is not known. In the present study, we take advantage of keratinocytes in culture. Using this in vitro model, we determined that IRF6 is necessary for the proper assembly of adherens junctions, tight junctions and desmosomes. Particularly, IRF6 is required for proper levels at the membrane of one of the components of adherens junctions, E-cadherin. We demonstrated that it is the recycling of E-cadherin, and not its endocytosis, that is affected by IRF6. To further explore the molecular mechanism by which IRF6 mediates recycling of E-cadherin at the membrane, we evaluated the requirement of the protein binding domain (PBD) and the DNA binding domain (DBD) of IRF6 in the regulation of cellular adhesions. We demonstrated that the PBD of IRF6 is necessary and sufficient for the recycling of E-cadherin. Furthermore, we performed mass spectrometry analysis to define the interactome of IRF6 and to identify the effector proteins acting downstream of IRF6 in the regulation of E-cadherin recycling. We show that IRF6 forms a complex with E-cadherin as well as with Rab11 in recycling endosomes, and the formation of this complex facilitates the exit of E-cadherin from the endosomal pathway towards the cell membrane. Thus, we define a non-canonical role for IRF6 in the regulation of cellular adhesions that requires its interaction with cytoplasmic effector proteins.
Details
- Title: Subtitle
- IRF6 regulates the recycling of E-cadherin at the cell membrane
- Creators
- Angelo Antiguas
- Contributors
- Martine Dunnwald (Advisor)Kris A. DeMali (Committee Member)Thomas Rutkowski (Committee Member)Charles Yeaman (Committee Member)Edward Sander (Committee Member)
- Resource Type
- Dissertation
- Degree Awarded
- Doctor of Philosophy (PhD), University of Iowa
- Degree in
- Biomedical Science (Cell and Developmental Biology)
- Date degree season
- Spring 2023
- DOI
- 10.25820/etd.007179
- Publisher
- University of Iowa
- Number of pages
- xiii, 124 pages
- Copyright
- Copyright 2022 Angelo Antiguas
- Language
- English
- Date submitted
- 03/19/2023
- Date approved
- 06/30/2023
- Description illustrations
- Illustrations, tables, graphs, charts
- Description bibliographic
- Includes bibliographical references (pages 99-124).
- Public Abstract (ETD)
Cellular adhesions connect neighboring cells allowing them to assemble in tissues to form organs. Therefore, understanding the mechanism by which cells form adhesions is critical to understand tissue morphogenesis. Interferon Regulatory Factor 6 (IRF6) is a protein that is necessary for the formation of the epithelium of the skin, however, the mechanism by which IRF6 regulates epithelial adhesions remains to be elucidated. In the present study we demonstrated that IRF6 forms interactions with other proteins to facilitate the recycling of cell adhesion components at the cell membrane.
- Academic Unit
- Biomedical Science Program; Craniofacial Anomalies Research Center
- Record Identifier
- 9984425392502771
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