{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T22:42:02Z","timestamp":1790635322931,"version":"4.1.0"},"reference-count":53,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,5,12]],"date-time":"2022-05-12T00:00:00Z","timestamp":1652313600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["FOR 2497 TP5"],"award-info":[{"award-number":["FOR 2497 TP5"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>The autoimmune dermatosis pemphigus foliaceus (PF) is predominantly caused by IgG autoantibodies against the desmosomal cadherin desmoglein (Dsg) 1. The exact mechanisms that lead to the characteristic epidermal blistering are not yet fully understood. In the present study, we used a variety of biophysical methods to examine the fate of membrane-bound Dsg1 after incubation with PF patients\u2019 IgG. Dispase-based dissociation assays confirmed that PF-IgG used for this study reduced intercellular adhesion in a manner dependent on phospholipase C (PLC)\/Ca<jats:sup>2+<\/jats:sup> and extracellular signal-regulated kinase (ERK) 1\/2 signaling. Atomic force microscopy (AFM) revealed that Dsg1 binding on single molecule level paralleled effects on keratinocyte adhesion under the different conditions. Stimulated emission depletion (STED) super-resolution microscopy was used to investigate the localization of Dsg1 after PF-IgG incubation for 24 h. Under control conditions, Dsg1 was found to be in part co-localized with desmoplakin and thus inside of desmosomes as well as extra-desmosomal along the cell border. Incubation with PF-IgG reduced the extra-desmosomal Dsg1 fraction. In line with this, fluorescence recovery after photobleaching (FRAP) experiments demonstrated a strongly reduced mobility of Dsg1 in the cell membrane after PF-IgG treatment indicating remaining Dsg1 molecules were primarily located inside desmosomes. Mechanistically, experiments confirmed the involvement of PLC\/Ca<jats:sup>2+<\/jats:sup> since inhibition of PLC or 1,4,5-trisphosphate (IP3) receptor to reduce cytosolic Ca<jats:sup>2+<\/jats:sup> reverted the effects of PF-IgG on Dsg1 intra-membrane mobility and localization. Taken together, our findings suggest that during the first 24 h PF-IgG induce redistribution predominantly of membrane-bound extradesmosomal Dsg1 in a PLC\/Ca<jats:sup>2+<\/jats:sup> dependent manner whereas Dsg1-containing desmosomes remain.<\/jats:p>","DOI":"10.3389\/fimmu.2022.882116","type":"journal-article","created":{"date-parts":[[2022,5,12]],"date-time":"2022-05-12T12:46:55Z","timestamp":1652359615000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":9,"title":["Pemphigus Foliaceus Autoantibodies Induce Redistribution Primarily of Extradesmosomal Desmoglein 1 in the Cell Membrane"],"prefix":"10.3389","volume":"13","author":[{"given":"Matthias","family":"Hiermaier","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniela","family":"Kugelmann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mariya Y.","family":"Radeva","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dario","family":"Didona","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kamran","family":"Ghoreschi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Solimani","family":"Farzan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Hertl","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jens","family":"Waschke","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,5,12]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"65","DOI":"10.3109\/15419061.2013.876018","article-title":"Desmosomal Adhesion In Vivo","volume":"21","author":"Berika","year":"2014","journal-title":"Cell Commun Adhes"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.037457","article-title":"Desmosomes at a Glance","volume":"122","author":"Desai","year":"2009","journal-title":"J Cell Sci"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbamem.2007.07.014","article-title":"Desmosome Structure, Composition and Function","volume":"1778","author":"Garrod","year":"2008","journal-title":"Biochim Biophys Acta"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1016\/j.jid.2017.08.033","article-title":"Keratins Regulate the Adhesive Properties of Desmosomal Cadherins Through Signaling","volume":"138","author":"Vielmuth","year":"2018","journal-title":"J Invest Dermatol"},{"key":"B5","doi-asserted-by":"publisher","first-page":"a002543","DOI":"10.1101\/cshperspect.a002543","article-title":"The Desmosome","volume":"1","author":"Delva","year":"2009","journal-title":"Cold Spring Harb Perspect Biol"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1016\/j.tcb.2013.06.004","article-title":"Desmosome Assembly and Dynamics","volume":"23","author":"Nekrasova","year":"2013","journal-title":"Trends Cell Biol"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.115.8.1717","article-title":"Desmosomes: Interconnected Calcium-Dependent Structures of Remarkable Stability With Significant Integral Membrane Protein Turnover","volume":"115","author":"Windoffer","year":"2002","journal-title":"J Cell Sci"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.3389\/fmed.2018.00226","article-title":"The Genetics of Pemphigus Vulgaris","volume":"226","author":"Vodo","year":"2018","journal-title":"Front Med"},{"key":"B9","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1007\/s12016-017-8662-z","article-title":"Pemphigus: A Comprehensive Review on Pathogenesis, Clinical Presentation and Novel Therapeutic Approaches","volume":"54","author":"Pollmann","year":"2018","journal-title":"Clin Rev Allergy Immunol"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.3389\/fmed.2018.00218","article-title":"The Evolving Story of Autoantibodies in Pemphigus Vulgaris: Development of the \u201cSuper Compensation Hypothesis\u201d","volume":"5","author":"Sinha","year":"2018","journal-title":"Front Med"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2018.01190","article-title":"Non-Desmoglein Antibodies in Patients With Pemphigus Vulgaris","volume":"9","author":"Amber","year":"2018","journal-title":"Front Immunol"},{"key":"B12","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/nrdp.2017.26","article-title":"Pemphigus","volume":"3","author":"Kasperkiewicz","year":"2017","journal-title":"Nat Rev Dis Primers"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(19)31778-7","article-title":"Pemphigus","volume":"394","author":"Schmidt","year":"2019","journal-title":"Lancet"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1172\/JCI115968","article-title":"Autoantibodies Against the Amino-Terminal Cadherin-Like Binding Domain of Pemphigus Vulgaris Antigen are Pathogenic","volume":"90","author":"Amagai","year":"1992","journal-title":"J Clin Invest"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1111\/bjd.15721","article-title":"Inhibition of P38mapk Signalling Prevents Epidermal Blistering and Alterations of Desmosome Structure Induced by Pemphigus Autoantibodies in Human Epidermis","volume":"177","author":"Egu","year":"2017","journal-title":"Br J Dermatol"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1172\/JCI144363","article-title":"Translational Implications of Th17-Skewed Inflammation Due to Genetic Deficiency of a Cadherin Stress Sensor","volume":"132","author":"Godsel","year":"2022","journal-title":"J Clin Invest"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1016\/j.jid.2019.01.002","article-title":"Desmoglein 1 Deficiency Causes Lethal Skin Blistering","volume":"139","author":"Kugelmann","year":"2019","journal-title":"J Invest Dermatol"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2021.745670","article-title":"Desmosomes as Signaling Hubs in the Regulation of Cell Behavior","volume":"9","author":"Muller","year":"2021","journal-title":"Front Cell Dev Biol"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1002\/med.21310","article-title":"Desmosomes and Extradesmosomal Adhesive Signaling Contacts in Pemphigus","volume":"34","author":"Waschke","year":"2014","journal-title":"Med Res Rev"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1111\/exd.14453","article-title":"Mechanism-Based Therapeutic Targets of Pemphigus Vulgaris: A Scoping Review of Pathogenic Molecular Pathways","volume":"31","author":"Kaur","year":"2021","journal-title":"Exp Dermatol"},{"key":"B21","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1111\/joa.13634","article-title":"Structure and Regulation of Desmosomes in Intercalated Discs: Lessons From Epithelia","author":"Yeruva","year":"2022","journal-title":"J Anat"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.3389\/fmed.2021.701809","article-title":"Autoantibody-Specific Signalling in Pemphigus","volume":"8","author":"Schmitt","year":"2021","journal-title":"Front Med (Lausanne)"},{"key":"B23","doi-asserted-by":"publisher","first-page":"595","DOI":"10.1111\/bjd.20091","article-title":"Ca(2+) Signalling is Critical for Autoantibody-Induced Blistering of Human Epidermis in Pemphigus","volume":"185","author":"Schmitt","year":"2021","journal-title":"Br J Dermatol"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.106.3.761","article-title":"Normal Keratinization in a Spontaneously Immortalized Aneuploid Human Keratinocyte Cell Line","volume":"106","author":"Boukamp","year":"1988","journal-title":"J Cell Biol"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1172\/JCI23475","article-title":"Pemphigus Foliaceus IgG Causes Dissociation of Desmoglein 1-Containing Junctions Without Blocking Desmoglein 1 Transinteraction","volume":"115","author":"Waschke","year":"2005","journal-title":"J Clin Invest"},{"key":"B26","doi-asserted-by":"publisher","first-page":"1219","DOI":"10.1016\/j.jid.2020.09.022","article-title":"The Actin-Binding Protein Alpha-Adducin Modulates Desmosomal Turnover and Plasticity","volume":"141","author":"Hiermaier","year":"2021","journal-title":"J Invest Dermatol"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1021\/bc070030s","article-title":"A New, Simple Method for Linking of Antibodies to Atomic Force Microscopy Tips","volume":"18","author":"Ebner","year":"2007","journal-title":"Bioconjug Chem"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0053739","article-title":"Desmoglein 2 is Less Important Than Desmoglein 3 for Keratinocyte Cohesion","volume":"8","author":"Hartlieb","year":"2013","journal-title":"PloS One"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1038\/227680a0","article-title":"Cleavage of Structural Proteins During the Assembly of the Head of Bacteriophage T4","volume":"227","author":"Laemmli","year":"1970","journal-title":"Nature"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.15252\/embj.201695709","article-title":"Glyoxal as an Alternative Fixative to Formaldehyde in Immunostaining and Super-Resolution Microscopy","volume":"37","author":"Richter","year":"2018","journal-title":"EMBO J"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2019.01128","article-title":"Role of Dsg1- and Dsg3-Mediated Signaling in Pemphigus Autoantibody-Induced Loss of Keratinocyte Cohesion","volume":"10","author":"Walter","year":"2019","journal-title":"Front Immunol"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1111\/j.0022-202X.2005.23714.x","article-title":"In Vitro Keratinocyte Dissociation Assay for Evaluation of the Pathogenicity of Anti-Desmoglein 3 IgG Autoantibodies in Pemphigus Vulgaris","volume":"124","author":"Ishii","year":"2005","journal-title":"J Invest Dermatol"},{"key":"B33","doi-asserted-by":"publisher","first-page":"387","DOI":"10.1007\/978-1-61779-207-6_26","article-title":"Fluorescence Recovery After Photobleaching","volume":"769","author":"Carisey","year":"2011","journal-title":"Methods Mol Biol"},{"key":"B34","doi-asserted-by":"publisher","first-page":"59","DOI":"10.1038\/JID.2015.353","article-title":"Super-Resolution Microscopy Reveals Altered Desmosomal Protein Organization in Tissue From Patients With Pemphigus Vulgaris","volume":"136","author":"Stahley","year":"2016","journal-title":"J Invest Dermatol"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2818.1993.tb03313.x","article-title":"Measurement of Co-Localization of Objects in Dual-Colour Confocal Images","volume":"169","author":"Manders","year":"1993","journal-title":"J Microsc"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M607963200","article-title":"Anti-Desmoglein 3 (Dsg3) Monoclonal Antibodies Deplete Desmosomes of Dsg3 and Differ in Their Dsg3-Depleting Activities Related to Pathogenicity","volume":"282","author":"Yamamoto","year":"2007","journal-title":"J Biol Chem"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1111\/ddg.14097_g","article-title":"S2k-Leitlinie Zur Therapie Des Pemphigus Vulgaris\/Foliaceus Und Des Bull\u00f6sen Pemphigoids: 2019 Update","volume":"18","author":"Schmidt","year":"2020","journal-title":"J Dtsch Dermatol Ges"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1111\/bph.15233","article-title":"Identification of Novel Therapeutic Targets for Blocking Acantholysis in Pemphigus","volume":"177","author":"Burmester","year":"2020","journal-title":"Br J Pharmacol"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1016\/j.jid.2017.06.022","article-title":"Mechanisms Causing Loss of Keratinocyte Cohesion in Pemphigus","volume":"138","author":"Spindler","year":"2018","journal-title":"J Invest Dermatol"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1111\/1523-1747.ep12319948","article-title":"Pharmacologic Evidence for Involvement of Phospholipase C in Pemphigus IgG-Induced Inositol 1,4,5-Trisphosphate Generation, Intracellular Calcium Increase, and Plasminogen Activator Secretion in DJM-1 Cells, a Squamous Cell Carcinoma Line","volume":"105","author":"Esaki","year":"1995","journal-title":"J Invest Dermatol"},{"key":"B41","doi-asserted-by":"publisher","first-page":"151904","DOI":"10.1016\/j.aanat.2022.151904","article-title":"Electron Microscopy Reveals That Phospholipase C and Ca(2+) Signaling Regulate Keratin Filament Uncoupling From Desmosomes in Pemphigus","volume":"241","author":"Egu","year":"2022","journal-title":"Ann Anat"},{"key":"B42","doi-asserted-by":"publisher","first-page":"3579","DOI":"10.1038\/s41598-017-03697-7","article-title":"Different Signaling Patterns Contribute to Loss of Keratinocyte Cohesion Dependent on Autoantibody Profile in Pemphigus","volume":"7","author":"Walter","year":"2017","journal-title":"Sci Rep"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1177\/039463200702000216","article-title":"Internalization of non-Clustered Desmoglein 1 Without Depletion of Desmoglein 1 From Adhesion Complexes in an Experimental Model of the Autoimmune Disease Pemphigus Foliaceus","volume":"20","author":"Lanza","year":"2007","journal-title":"Int J Immunopathol Pharmacol"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1002\/jcp.20856","article-title":"Changes in Desmoglein 1 Expression and Subcellular Localization in Cultured Keratinocytes Subjected to Anti-Desmoglein 1 Pemphigus Autoimmunity","volume":"210","author":"Cirillo","year":"2007","journal-title":"J Cell Physiol"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2018.00528","article-title":"Keratins Regulate P38mapk-Dependent Desmoglein Binding Properties in Pemphigus","volume":"9","author":"Vielmuth","year":"2018","journal-title":"Front Immunol"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1111\/exd.13106","article-title":"Monopathogenic vs Multipathogenic Explanations of Pemphigus Pathophysiology","volume":"25","author":"Ahmed","year":"2016","journal-title":"Exp Dermatol"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20022031","article-title":"The Role of Intramolecular Epitope Spreading in the Pathogenesis of Endemic Pemphigus Foliaceus (Fogo Selvagem)","volume":"197","author":"Li","year":"2003","journal-title":"J Exp Med"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.200605125","article-title":"Inhibition of Rho A Activity Causes Pemphigus Skin Blistering","volume":"175","author":"Waschke","year":"2006","journal-title":"J Cell Biol"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajpath.2011.06.043","article-title":"The Extent of Desmoglein 3 Depletion in Pemphigus Vulgaris is Dependent on Ca(2+)-Induced Differentiation: A Role in Suprabasal Epidermal Skin Splitting","volume":"179","author":"Spindler","year":"2011","journal-title":"Am J Pathol"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2020.00430","article-title":"Adrenergic Signaling-Induced Ultrastructural Strengthening of Intercalated Discs via Plakoglobin Is Crucial for Positive Adhesiotropy in Murine Cardiomyocytes","volume":"11","author":"Yeruva","year":"2020","journal-title":"Front Physiol"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.116.309631","article-title":"Adrenergic Signaling Strengthens Cardiac Myocyte Cohesion","volume":"120","author":"Schinner","year":"2017","journal-title":"Circ Res"},{"key":"B52","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.201906153","article-title":"Protein Exchange is Reduced in Calcium-Independent Epithelial Junctions","volume":"219","author":"Bartle","year":"2020","journal-title":"J Cell Biol"},{"key":"B53","doi-asserted-by":"publisher","DOI":"10.3109\/15419061.2014.943397","article-title":"150(Th) Anniversary Series: Desmosomes and Autoimmune Disease, Perspective of Dynamic Desmosome Remodeling and its Impairments in Pemphigus","volume":"21","author":"Kitajima","year":"2014","journal-title":"Cell Commun Adhes"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2022.882116\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,5,12]],"date-time":"2022-05-12T12:46:57Z","timestamp":1652359617000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2022.882116\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,5,12]]},"references-count":53,"alternative-id":["10.3389\/fimmu.2022.882116"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2022.882116","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,5,12]]},"article-number":"882116"}}