In pemphigus vulgaris, a life-threatening autoimmune skin disease, epidermal blisters are caused by autoantibodies primarily targeting desmosomal cadherins desmoglein 3 (DSG3) and DSG1, leading to loss of keratinocyte cohesion. Due to limited insights into disease pathogenesis, current therapy relies primarily on nonspecific long-term immunosuppression. Both direct inhibition of DSG transinteraction and altered intracellular signaling by p38 MAPK likely contribute to the loss of cell adhesion. Here, we applied a tandem peptide (TP) consisting of 2 connected peptide sequences targeting the DSG adhesive interface that was capable of blocking autoantibody-mediated direct interference of DSG3 transinteraction, as revealed by atomic force microscopy and optical trapping. Importantly, TP abrogated autoantibody-mediated skin blistering in mice and was effective when applied topically. Mechanistically, TP inhibited both autoantibody-induced p38 MAPK activation and its association with DSG3, abrogated p38 MAPK-induced keratin filament retraction, and promoted desmosomal DSG3 oligomerization. These data indicate that p38 MAPK links autoantibody-mediated inhibition of DSG3 binding to skin blistering. By limiting loss of DSG3 transinteraction, p38 MAPK activation, and keratin filament retraction, which are hallmarks of pemphigus pathogenesis, TP may serve as a promising treatment option.
Volker Spindler, Vera Rötzer, Carina Dehner, Bettina Kempf, Martin Gliem, Mariya Radeva, Eva Hartlieb, Gregory S. Harms, Enno Schmidt, Jens Waschke
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The impact of signaling pathways on the desmosome ultrastructure in pemphigus
Schmitt T, Huber J, Pircher J, Schmidt E, Waschke J |
Frontiers in Immunology | 2025 |
Meeting report – Alpine desmosome disease meeting 2024: advances and emerging topics in desmosomes and related diseases
Waschke J, Amagai M, Becker C, Delmar M, Duru F, Garrod DR, Gerull B, Green KJ, Hertl M, Kowalczyk AP, Niessen CM, Nusrat A, Schinner C, Schlegel N, Sivasankar S, Vielmuth F, Spindler V |
Journal of Cell Science | 2025 |
Role of auto-antibodies in the mechanisms of dengue pathogenesis and its progression: a comprehensive review.
Ghorai T, Sarkar A, Roy A, Bhowmick B, Nayak D, Das S |
Archives of Microbiology | 2024 |
Adhesion of pancreatic tumor cell clusters by desmosomal molecules enhances early liver metastases formation.
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Scientific Reports | 2024 |
Apremilast prevents blistering in human epidermis and stabilizes keratinocyte adhesion in pemphigus.
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Nature Communications | 2023 |
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Schmitt T, Hudemann C, Moztarzadeh S, Hertl M, Tikkanen R, Waschke J |
Frontiers in immunology | 2023 |
Mouse models of pemphigus: valuable tools to investigate pathomechanisms and novel therapeutic interventions
Emtenani S, Hertl M, Schmidt E, Hudemann C |
Frontiers in immunology | 2023 |
Desmosomal Cadherins in Health and Disease
M Hegazy, A Perl, S Svoboda, K Green |
Annual review of pathology | 2022 |
Desmoglein 2 can undergo Ca2+-dependent interactions with both desmosomal and classical cadherins including E-cadherin and N-cadherin
M Fuchs, D Kugelmann, N Schlegel, F Vielmuth, J Waschke |
Biophysical Journal | 2022 |
Mechanisms Causing Acantholysis in Pemphigus-Lessons from Human Skin
Egu DT, Schmitt T, Waschke J |
Frontiers in immunology | 2022 |
Unmet Medical Needs in Chronic, Non-communicable Inflammatory Skin Diseases
Ujiie H, Rosmarin D, Schön MP, Ständer S, Boch K, Metz M, Maurer M, Thaci D, Schmidt E, Cole C, Amber KT, Didona D, Hertl M, Recke A, Graßhoff H, Hackel A, Schumann A, Riemekasten G, Bieber K, Sprow G, Dan J, Zillikens D, Sezin T, Christiano AM, Wolk K, Sabat R, Kridin K, Werth VP, Ludwig RJ |
Frontiers in Medicine | 2022 |
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Kugelmann D, Anders M, Sigmund AM, Egu DT, Eichkorn RA, Yazdi AS, Sárdy M, Hertl M, Didona D, Hashimoto T, Waschke J |
Frontiers in immunology | 2022 |
Structure and regulation of desmosomes in intercalated discs: Lessons from epithelia
Yeruva S, Waschke J |
Journal of Anatomy | 2022 |
Autoantibody-Specific Signalling in Pemphigus
T Schmitt, J Waschke |
Frontiers in Medicine | 2021 |
Cadherin Signaling in Cancer and Autoimmune Diseases
M Sisto, D Ribatti, S Lisi |
International journal of molecular sciences | 2021 |
Stabilization of desmoglein-2 binding rescues arrhythmia in arrhythmogenic cardiomyopathy
Camilla Schinner, Bernd Markus Erber, Sunil Yeruva, Angela Schlipp, Vera Rötzer, Ellen Kempf, Sebastian Kant, Rudolf Leube, Thomas D. Mueller, Jens Waschke |
JCI Insight | 2020 |
Cardiomyocyte adhesion and hyper-adhesion differentially require ERK1/2 and plakoglobin.
Maria Shoykhet, Sebastian Trenz, Ellen Kempf, Tatjana Williams, Brenda Gerull, Camilla Schinner, Sunil Yeruva, Jens Waschke |
JCI Insight | 2020 |
Identification of novel therapeutic targets for blocking acantholysis in pemphigus
IA Burmester, S Flaswinkel, CS Thies, A Kasprick, M Kamaguchi, V BumillerBini, S Emtenani, N Feldmann, K Kridin, E Schmidt, N Beek, D Zillikens, CM Hammers, JE Hundt, RJ Ludwig |
British Journal of Pharmacology | 2020 |
The inotropic agent digitoxin strengthens desmosomal adhesion in cardiac myocytes in an ERK1/2-dependent manner
C Schinner, S Olivares-Florez, A Schlipp, S Trenz, M Feinendegen, H Flaswinkel, E Kempf, DT Egu, S Yeruva, J Waschke |
Basic Research in Cardiology | 2020 |
Current Clinical Trials in Pemphigus and Pemphigoid
K Izumi, K Bieber, RJ Ludwig |
Frontiers in immunology | 2019 |
Role of Dsg1- and Dsg3-Mediated Signaling in Pemphigus Autoantibody-Induced Loss of Keratinocyte Cohesion
E Walter, F Vielmuth, MT Wanuske, M Seifert, R Pollmann, R Eming, J Waschke |
Frontiers in immunology | 2019 |
Role of Src and Cortactin in Pemphigus Skin Blistering
D Kugelmann, V Rötzer, E Walter, DT Egu, MT Fuchs, F Vielmuth, H Vargas-Robles, M Schnoor, M Hertl, R Eming, K Rottner, A Schmidt, V Spindler, J Waschke |
Frontiers in immunology | 2019 |
Plakophilin 1 but not plakophilin 3 regulates desmoglein clustering
M Fuchs, M Foresti, MY Radeva, D Kugelmann, R Keil, M Hatzfeld, V Spindler, J Waschke, F Vielmuth |
Cellular and Molecular Life Sciences | 2019 |
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N van Beek, D Zillikens, E Schmidt |
Der Hautarzt | 2019 |
Pemphigus: a Comprehensive Review on Pathogenesis, Clinical Presentation and Novel Therapeutic Approaches
R Pollmann, T Schmidt, R Eming, M Hertl |
Clinical Reviews in Allergy & Immunology | 2018 |
Atomic Force Microscopy Provides New Mechanistic Insights into the Pathogenesis of Pemphigus
F Vielmuth, V Spindler, J Waschke |
Frontiers in immunology | 2018 |
Keratins Regulate p38MAPK-Dependent Desmoglein Binding Properties in Pemphigus
F Vielmuth, E Walter, M Fuchs, MY Radeva, F Buechau, TM Magin, V Spindler, J Waschke |
Frontiers in immunology | 2018 |
Keratin Retraction and Desmoglein3 Internalization Independently Contribute to Autoantibody-Induced Cell Dissociation in Pemphigus Vulgaris
E Schlögl, MY Radeva, F Vielmuth, C Schinner, J Waschke, V Spindler |
Frontiers in immunology | 2018 |
Autoantibody Signaling in Pemphigus Vulgaris: Development of an Integrated Model
T Sajda, AA Sinha |
Frontiers in immunology | 2018 |
Pemphigus—A Disease of Desmosome Dysfunction Caused by Multiple Mechanisms
V Spindler, J Waschke |
Frontiers in immunology | 2018 |
Immunoadsorption of Desmoglein-3-Specific IgG Abolishes the Blister-Inducing Capacity of Pemphigus Vulgaris IgG in Neonatal Mice
M Hofrichter, J Dworschak, S Emtenani, J Langenhan, F Weiß, L Komorowski, D Zillikens, W Stöcker, C Probst, E Schmidt, S Goletz |
Frontiers in immunology | 2018 |
Setting the target for pemphigus vulgaris therapy
Christoph Ellebrecht, Aimee S. Payne |
JCI Insight | 2017 |
Mechanisms of Autoantibody-Induced Pathology
RJ Ludwig, K Vanhoorelbeke, F Leypoldt, Z Kaya, K Bieber, SM McLachlan, L Komorowski, J Luo, O Cabral-Marques, CM Hammers, JM Lindstrom, P Lamprecht, A Fischer, G Riemekasten, C Tersteeg, P Sondermann, B Rapoport, KP Wandinger, C Probst, AE Beidaq, E Schmidt, A Verkman, RA Manz, F Nimmerjahn |
Frontiers in immunology | 2017 |
Peptide mimetics of immunoglobulin A (IgA) and FcαRI block IgA-induced human neutrophil activation and migration
MH Heineke, LP van der Steen, RM Korthouwer, JJ Hage, JP Langedijk, JJ Benschop, JE Bakema, JW Slootstra, M Egmond |
European Journal of Immunology | 2017 |
Different signaling patterns contribute to loss of keratinocyte cohesion dependent on autoantibody profile in pemphigus
E Walter, F Vielmuth, L Rotkopf, M Sárdy, ON Horváth, M Goebeler, E Schmidt, R Eming, M Hertl, V Spindler, J Waschke |
Scientific Reports | 2017 |
Crosstalk between Signaling Pathways in Pemphigus: A Role for Endoplasmic Reticulum Stress in p38 Mitogen-Activated Protein Kinase Activation?
GA Cipolla, JK Park, RM Lavker, ML Petzl-Erler |
Frontiers in immunology | 2017 |
Desmoglein 2 regulates the intestinal epithelial barrier via p38 mitogen-activated protein kinase
H Ungewiß, F Vielmuth, ST Suzuki, A Maiser, H Harz, H Leonhardt, D Kugelmann, N Schlegel, J Waschke |
Scientific Reports | 2017 |
Mechanisms of Disease: Pemphigus and Bullous Pemphigoid
CM Hammers, JR Stanley |
Annual review of pathology | 2016 |
Meibomian gland cells display a differentiation-dependent composition of desmosomes
V Rötzer, D Egu, J Waschke |
Histochemistry and Cell Biology | 2016 |
Loss of Desmoglein Binding Is Not Sufficient for Keratinocyte Dissociation in Pemphigus
F Vielmuth, J Waschke, V Spindler |
Journal of Investigative Dermatology | 2015 |
Pemphigus: Modellerkrankung für zielgerichtete Therapien
R Eming |
Der Hautarzt | 2015 |
F-actin binding protein, anillin, regulates integrity of intercellular junctions in human epithelial cells
D Wang, GK Chadha, A Feygin, AI Ivanov |
Cellular and Molecular Life Sciences | 2015 |
E-cadherin and Src associate with extradesmosomal Dsg3 and modulate desmosome assembly and adhesion
V Rötzer, E Hartlieb, F Vielmuth, M Gliem, V Spindler, J Waschke |
Cellular and Molecular Life Sciences | 2015 |
Immature truncated O-glycophenotype of cancer directly induces oncogenic features
P Radhakrishnan, S Dabelsteen, FB Madsen, C Francavilla, KL Kopp, C Steentoft, SY Vakhrushev, JV Olsen, L Hansen, EP Bennett, A Woetmann, G Yin, L Chen, H Song, M Bak, RA Hlady, SL Peters, R Opavsky, C Thode, K Qvortrup, KT Schjoldager, H Clausen, MA Hollingsworth, HH Wandall |
Proceedings of the National Academy of Sciences | 2014 |
Adducin Is Required for Desmosomal Cohesion in Keratinocytes
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The Journal of biological chemistry | 2014 |
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Cold Spring Harbor Perspectives in Medicine | 2014 |
From Epidemiology and Genetics to Diagnostics, Outcome Measures, and Novel Treatments in Autoimmune Bullous Diseases
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A New Light on an Old Disease: Adhesion Signaling in Pemphigus Vulgaris
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Plakophilins, Desmogleins, and Pemphigus: The Tail Wagging the Dog
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Desmoglein 2 Compensates for Desmoglein 3 but Does Not Control Cell Adhesion via Regulation of p38 Mitogen-activated Protein Kinase in Keratinocytes
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The Journal of biological chemistry | 2014 |
p38 MAPK Signaling in Pemphigus: Implications for Skin Autoimmunity
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Autoimmune Diseases | 2013 |
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Journal of Investigative Dermatology | 2013 |