Desmosomes are cell-cell adhesion structures that are required for the mechanical strength of the epidermis. Disruption of desmosomes results in devastating effects on skin integrity in diseases including pemphigus vulgaris/foliaceus and some types of epidermolysis bullosa. Mutations in desmosomal proteins also lead to cardiomyopathies/dysplasias. Our long-term goal is to understand the assembly and functions of desmosomes and the cellular responses to their disruption. The canonical function of desmosomes is to physically link keratin networks between cells. While we have a good understanding of the direct physical interactions that mediate keratin attachment, it is not known whether desmosomes affect keratin assembly. We have identified a novel desmosomal protein with the unique ability to promote the local assembly of keratin filaments. This changes our view of desmosomes from relatively passive structures that simply bind cytoskeletal networks to active modulators of their assembly. We will study the mechanism and regulation of this remarkable activity, which is expected to identify a novel pathway for desmosome stability and epidermal integrity.
Our second aim will use a targeted proteomics approach to identify novel and transiently associated desmosomal proteins. This will identify additional putative disease genes and allow future quantitative determination of changes in desmosome composition in various disease states. Finally, our third aim addresses cellular responses to loss of desmosomes. We have found that desmosome disruption leads to dramatic changes in adherens and tight junction activity through effects on protein expression and localization. We will determine how cells sense desmosome disruption and determine the signaling pathways that control alterations of other cell adhesion structures. In total, these studies will increase or understanding of normal desmosome function and cellular responses to their perturbation which we expect to yield diagnostic and therapeutic tools for desmosome-related diseases.

Public Health Relevance

The skin provides an essential barrier to the outside world. The mechanical stability of the skin requires cells to stick strongly together through structures called desmosomes. Loss of desmosomes, which occurs in genetic, autoimmune, and bacterial diseases, results in skin blistering. Our work will increase our understanding of how desmosomes normally form and how the epidermis responds to the loss of desmosome function. These studies are expected to yield novel diagnostic and therapeutic targets for pemphigus and other blistering diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR055926-08
Application #
9277998
Study Section
Intercellular Interactions Study Section (ICI)
Program Officer
Cibotti, Ricardo
Project Start
2009-08-01
Project End
2020-06-30
Budget Start
2017-07-01
Budget End
2018-06-30
Support Year
8
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Duke University
Department
Dermatology
Type
Schools of Medicine
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705
Muroyama, Andrew; Terwilliger, Michael; Dong, Bushu et al. (2018) Genetically induced microtubule disruption in the mouse intestine impairs intracellular organization and transport. Mol Biol Cell 29:1533-1541
Sumigray, Kaelyn D; Terwilliger, Michael; Lechler, Terry (2018) Morphogenesis and Compartmentalization of the Intestinal Crypt. Dev Cell 45:183-197.e5
Muroyama, Andrew; Lechler, Terry (2017) A transgenic toolkit for visualizing and perturbing microtubules reveals unexpected functions in the epidermis. Elife 6:
Muroyama, Andrew; Lechler, Terry (2017) Microtubule organization, dynamics and functions in differentiated cells. Development 144:3012-3021
Seldin, Lindsey; Muroyama, Andrew; Lechler, Terry (2016) NuMA-microtubule interactions are critical for spindle orientation and the morphogenesis of diverse epidermal structures. Elife 5:
Sumigray, Kaelyn D; Lechler, Terry (2015) Cell adhesion in epidermal development and barrier formation. Curr Top Dev Biol 112:383-414
Zhou, Kang; Sumigray, Kaelyn D; Lechler, Terry (2015) The Arp2/3 complex has essential roles in vesicle trafficking and transcytosis in the mammalian small intestine. Mol Biol Cell 26:1995-2004
Morrow, Angel; Lechler, Terry (2015) Studying cell biology in the skin. Mol Biol Cell 26:4183-6
Huebner, Robert J; Lechler, Terry; Ewald, Andrew J (2014) Developmental stratification of the mammary epithelium occurs through symmetry-breaking vertical divisions of apically positioned luminal cells. Development 141:1085-94
Lechler, Terry (2014) Arp2/3 complex function in the epidermis. Tissue Barriers 2:e944445

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