Plakophilin-1 protects keratinocytes from pemphigus vulgaris IgG by forming calcium-independent desmosomes.
Plakophilin-1 (PKP-1) is an armadillo family protein critical for desmosomal adhesion and epidermal integrity. In the autoimmune skin-blistering disease pemphigus vulgaris (PV), autoantibodies (IgG) target the desmosomal cadherin desmoglein 3 (Dsg3) and compromise keratinocyte cell-cell adhesion. Here, we report that enhanced expression of PKP-1 protects keratinocytes from PV IgG-induced loss of cell-cell adhesion. PKP-1 prevents loss of Dsg3 and other desmosomal proteins from cell-cell borders and prevents alterations in desmosome ultrastructure in keratinocytes treated with PV IgG. Using a series of Dsg3 chimeras and deletion constructs, we find that PKP-1 clusters Dsg3 with the desmosomal plaque protein desmoplakin in a manner dependent on the plakoglobin-binding domain of the Dsg3 tail. Furthermore, PKP-1 expression transforms desmosome adhesion from a calcium-dependent to a calcium-independent and hyperadhesive state. These results demonstrate that manipulating the expression of a single desmosomal plaque protein can block the pathogenic effects of PV IgG on keratinocyte adhesion.
Department of Cell Biology, Emory University, Atlanta, Georgia, USA; Graduate Program in Biochemistry, Cell, and Developmental Biology, Emory University, Atlanta, Georgia, USA.
Dana K
DK
Tucker
Department of Cell Biology, Emory University, Atlanta, Georgia, USA; Graduate Program in Biochemistry, Cell, and Developmental Biology, Emory University, Atlanta, Georgia, USA.
Sara N
SN
Stahley
Department of Cell Biology, Emory University, Atlanta, Georgia, USA; Department of Dermatology, Emory University, Atlanta, Georgia, USA; Winship Cancer Institute, Emory University, Atlanta, Georgia, USA. Electronic address: akowalc@emory.edu.
Andrew P
AP
Kowalczyk
D002118:Calcium / Q000737:chemistry*; D002448:Cell Adhesion; D002478:Cells, Cultured; D002614:Chelating Agents / Q000737:chemistry; D051184:Desmoglein 3 / Q000737:chemistry; D003896:Desmosomes / Q000378:metabolism*; D003902:Detergents / Q000737:chemistry; D004705:Endocytosis; D004817:Epidermis / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D007074:Immunoglobulin G / Q000737:chemistry*; D015603:Keratinocytes / Q000166:cytology*; D010392:Pemphigus / Q000276:immunology / Q000378:metabolism*; D051191:Plakophilins / Q000378:metabolism*
D002614:Chelating Agents; D051184:Desmoglein 3; D003902:Detergents; D007074:Immunoglobulin G; C495335:PKP1 protein, human; D051191:Plakophilins; D002118:Calcium