Determining the Cellular Mechanism Involved in Pemphigus Vulgaris-Induced Desmoglein 3 Internalization and Desmosomal Disassembly Open Access

Delva, Emmanuella (2009)

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Desmosomes are electron-dense intercellular adhesive complexes, responsible for
maintaining tissue integrity in organs subjected to mechanical stress. They are composed
of three families of proteins: the desmosomal cadherins, desmogleins and desmocollins;
the armadillo plaque proteins, plakoglobin and plakophilin; and the plakin family of
proteins, such as desmoplakin. Together, these proteins tether keratin intermediate
filaments to the plasma membrane.

In the autoimmune epidermal blistering disease, pemphigus vulgaris (PV), the
autoantibodies primarily target one of the desmosomal cadherins, desmoglein 3 (Dsg3)
and in some cases desmoglein 1 (Dsg1). As a result, Dsg3 is internalized, where it enters
an endo-lysosomal pathway for degradation. This degradation is associated with
retraction of the keratin filaments, mislocalization of desmoplakin, and overall loss of
cell-cell adhesion. The first part of the thesis focuses on determining the endocytic
machinery involved in PV-induced Dsg3 internalization. The work reported here
illustrates that Dsg3 internalization is mediated through a non-classical pathway,
independent of clathrin and dynamin. Furthermore, inhibition of Dsg3 endocytosis
prevents desmosomal disassembly. These findings, along with previous studies,
demonstrate that the internalization of Dsg3 is tightly coupled to desmosomal
disassembly in response to PV IgG.

The second part of the thesis addresses the role of the cytoskeletal network, in
particular the actin filaments and microtubules, in regulating PV-induced Dsg3
internalization, as studies have implicated a role for the cytoskeleton in vesicular
transport. Our preliminary findings suggest that depolymerizing actin results in increased
accumulation of Dsg3 in the cytoplasm. Furthermore, depolymerizing microtubules
prevents the initial entry of Dsg3 into the cell. These findings suggest that microtubules
and actin provide tracks by which Dsg3-containing vesicles are transported from the
plasma membrane to early endosomes and from early endosomes to lysosomes,

Altogether, these studies shed light on the cellular mechanism involved in the
desmosomal disassembly and epidermal blistering in response to PV. Moreover, these
data underscore the importance of regulating the intricate balance between desmosomal
assembly and disassembly, which is important in both the context of pathologies affected
by compromised cell-cell adhesion, such as PV, and in normal cellular processes, such as
cellular motility, cell morphology, proliferation and differentiation.

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