Pemphigus vulgaris IgG-induced desmoglein-3 endocytosis and desmosomal disassembly are mediated by a clathrin- and dynamin-independent mechanism.
Pemphigus vulgaris (PV) is a life-threatening autoimmune disease characterized by oral mucosal erosions and epidermal blistering. The autoantibodies generated target the desmosomal cadherin desmoglein-3 (Dsg3). Previous studies demonstrate that upon PV IgG binding, Dsg3 is internalized and enters an endo-lysosomal pathway where it is degraded. To define the endocytic machinery involved in PV IgG-induced Dsg3 internalization, human keratinocytes were incubated with PV IgG, and various tools were used to perturb distinct endocytic pathways. The PV IgG.Dsg3 complex failed to colocalize with clathrin, and inhibitors of clathrin- and dynamin-dependent pathways had little or no effect on Dsg3 internalization. In contrast, cholesterol binding agents such as filipin and nystatin and the tyrosine kinase inhibitor genistein dramatically inhibited Dsg3 internalization. Furthermore, the Dsg3 cytoplasmic tail specified sensitivity to these inhibitors. Moreover, inhibition of Dsg3 endocytosis with genistein prevented disruption of desmosomes and loss of adhesion in the presence of PV IgG. Altogether, these results suggest that PV IgG-induced Dsg3 internalization is mediated through a clathrin- and dynamin-independent pathway and that Dsg3 endocytosis is tightly coupled to the pathogenic activity of PV IgG.
Delva
Emmanuella
E
Graduate Program in Biochemistry, Cell, and Developmental Biology, Department of Cell Biology, Emory University, Atlanta, GA 30332, USA.
Jennings
Jean Marie
JM
Calkins
Cathárine C
CC
Kottke
Margaret D
MD
Faundez
Victor
V
Kowalczyk
Andrew P
AP
D002448:Cell Adhesion; D002478:Cells, Cultured; D002966:Clathrin / Q000737:chemistry*; D003593:Cytoplasm / Q000378:metabolism; D051184:Desmoglein 3 / Q000737:chemistry*; D034281:Dynamins / Q000737:chemistry*; D004705:Endocytosis; D005786:Gene Expression Regulation; D019833:Genistein / Q000494:pharmacology; D006801:Humans; D007074:Immunoglobulin G / Q000737:chemistry*; D015603:Keratinocytes / Q000166:cytology / Q000378:metabolism; D010392:Pemphigus / Q000276:immunology*; D011485:Protein Binding; D011505:Protein-Tyrosine Kinases / Q000378:metabolism
D002966:Clathrin; D051184:Desmoglein 3; D007074:Immunoglobulin G; D019833:Genistein; D011505:Protein-Tyrosine Kinases; D034281:Dynamins