title: Desmoglein versus non-desmoglein signaling in pemphigus acantholysis: characterization of novel signaling pathways downstream of pemphigus vulgaris antigens.
abstract: Although it is accepted that pemphigus antibody binding to keratinocytes (KCs) evokes an array of intracellular biochemical events resulting in cell detachment and death, the triggering events remain obscure. It has been postulated that the binding of pemphigus vulgaris IgG (PVIgG) to KCs induces "desmosomal" signaling. Because in contrast to integrins and classical cadherins, desmoglein (Dsg) molecules are not known to elicit intracellular signaling, and because PV patients also produce non-Dsg autoantibodies, we investigated the roles of both Dsg and non-desmoglein PV antigens. The time course studies of KCs treated with PVIgG demonstrated that the activity of Src peaked at 30 min, EGF receptor kinase (EGFRK) at 60 min, and p38 MAPK at 240 min. The Src inhibitor PP2 decreased EGFRK and p38 activities by approximately 45 and 30%, respectively, indicating that in addition to Src, PVIgG evokes other triggering events. The shrinkage of KCs (cell volume reduction) became significant at 120 min, keratin aggregation at 240 min, and an increase of TUNEL positivity at 360 min. Pretreatment of KCs with PP2 blocked PVIgG-dependent cell shrinkage and keratin aggregation by approximately 50% and TUNEL positivity by approximately 25%. The p38 MAPK inhibitor PD169316 inhibited these effects by approximately 15, 20, and 70%, respectively. Transfection of KCs with small interfering RNAs that silenced expression of Dsg1 and/or Dsg3 proteins, blocked approximately 50% of p38 MAPK activity but did not significantly alter the PVIgG-dependent rise in Src and EGFRK activities. These results indicate that activation of p38 MAPK is a late signaling step associated with collapse of the cytoskeleton and disassembly of desmosomes caused by upstream events involving Src and EGFRK. Therefore, the early acantholytic events are triggered by non-Dsg antibodies.
authors.affiliation: Department of Dermatology, University of California, Davis, California 95816, USA.
authors.forename: Alex I
authors.initials: AI
authors.lastname: Chernyavsky
authors.forename: Juan
authors.initials: J
authors.lastname: Arredondo
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Kitajima
authors.forename: Miki
authors.initials: M
authors.lastname: Sato-Nagai
authors.forename: Sergei A
authors.initials: SA
authors.lastname: Grando
mesh_terms: D000051:Acantholysis / Q000276:immunology / Q000473:pathology; D000941:Antigens / Q000276:immunology*; D001323:Autoantibodies / Q000276:immunology / Q000494:pharmacology; D002448:Cell Adhesion / Q000187:drug effects / Q000276:immunology; D048430:Cell Shape / Q000187:drug effects / Q000276:immunology; D002478:Cells, Cultured; D003599:Cytoskeleton / Q000276:immunology / Q000473:pathology; D053938:DNA Fragmentation / Q000187:drug effects; D051183:Desmoglein 1 / Q000276:immunology*; D051301:Desmoglein 2 / Q000276:immunology*; D003896:Desmosomes / Q000276:immunology / Q000473:pathology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D066246:ErbB Receptors; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D015603:Keratinocytes / Q000276:immunology* / Q000473:pathology; D007633:Keratins / Q000276:immunology; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000276:immunology*; D010392:Pemphigus / Q000276:immunology* / Q000473:pathology; D011743:Pyrimidines / Q000494:pharmacology; D013997:Time Factors; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000276:immunology; D019061:src-Family Kinases / Q000037:antagonists & inhibitors / Q000276:immunology
chemical_list: C412373:AG 1879; D000941:Antigens; D001323:Autoantibodies; C495297:DSG1 protein, human; C495314:DSG2 protein, human; D051183:Desmoglein 1; D051301:Desmoglein 2; D004791:Enzyme Inhibitors; D007093:Imidazoles; D011743:Pyrimidines; D007633:Keratins; D066246:ErbB Receptors; D019061:src-Family Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C408604:2-(4-nitrophenyl)-4-(4-fluorophenyl)-5-(4-pyridinyl)-1H-imidazole