Loss of the desmosomal protein perp enhances the phenotypic effects of pemphigus vulgaris autoantibodies.
Pemphigus vulgaris (PV) is an autoimmune bullous disease in which autoantibodies against proteins of the desmosomal adhesion complex perturb desmosomal function, leading to intercellular adhesion defects in the oral mucosa and skin. Previous studies have demonstrated a central role for downregulation of the desmosomal cadherin desmoglein 3 (DSG3) in the pathogenesis of PV. However, the effects of non-cadherin desmosomal proteins in modulating the cellular manifestations of PV remain poorly understood. Here, we characterize the expression and functional importance of Perp, a newly discovered tetraspan desmosomal protein, in PV. Our data demonstrate that PV autoantibodies disrupt Perp expression at the membrane and trigger its internalization along with DSG3 into the endosomal pathway, where it is ultimately targeted to the lysosome for degradation. We further show that Perp deficiency exacerbates the pathogenic effects of PV autoantibodies on keratinocytes by enhancing both the depletion of desmosomal DSG3 and intercellular adhesion defects. Together, our findings highlight the importance of non-cadherin desmosomal proteins in modulating PV phenotypes and provide new insight into Perp's role in the desmosome.
Nguyen
Bichchau
B
Division of Radiation and Cancer Biology, Department of Radiation Oncology, Stanford University School of Medicine, Stanford, California 94305-5152, USA.
Dusek
Rachel L
RL
Beaudry
Veronica G
VG
Marinkovich
M Peter
MP
Attardi
Laura D
LD
D000818:Animals; D001323:Autoantibodies / Q000276:immunology*; D002448:Cell Adhesion / Q000276:immunology; D002478:Cells, Cultured; D051184:Desmoglein 3 / Q000276:immunology / Q000378:metabolism; D003896:Desmosomes / Q000276:immunology* / Q000378:metabolism; D011992:Endosomes / Q000276:immunology; D016147:Genes, Tumor Suppressor; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology; D015603:Keratinocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008817:Mice, Mutant Strains; D010392:Pemphigus / Q000276:immunology* / Q000378:metabolism / Q000503:physiopathology; D010641:Phenotype
D001323:Autoantibodies; C071894:DSG3 protein, human; D051184:Desmoglein 3; C495300:Dsg3 protein, mouse; D007074:Immunoglobulin G; D008565:Membrane Proteins; C416404:PERP protein, human; C406964:Perp protein, mouse