In pemphigus, cell detachment, but not autoantibody binding, induces cell-wide, long-lasting transcriptomic and proteomic changes

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Bibliografiske detaljer
Udgivet i:	bioRxiv (Feb 12, 2025)
Hovedforfatter:	Hartmann, Veronika
Andre forfattere:	Sen, Guo, Rahimi, Siavash, Radine, Uta, Malheiros, Danielle, Salviano-Silva, Amanda, Valeria Bumiller-Bini Hoch, Cipolla, Gabriel A, Calonga-Solis, Veronica, Künstner, Axel, Burmester, Imke, Ludwig, Ralf J, William Vj Hariton, Hammers, Christoph M, Müller, Eliane J, Busch, Hauke, Hundt, Jennifer E
Udgivet:	Cold Spring Harbor Laboratory Press
Fag:	Transcriptomes Desmoglein 1 Cell adhesion molecules Desmoglein 3 Gene expression Keratinocytes Cell culture MAP kinase Organ culture Immunoglobulin G Wounding Proteomes NF-κB protein Cell differentiation Transcriptomics Autoantibodies Cellular stress response γ-Interferon Proteomics Pemphigus
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Beskrivelse
Resumen:	Desmoglein 1 (DSG1) and desmoglein 3 (DSG3) are adhesion molecules that maintain intercellular connections between epidermal, hair follicle, and mucosal keratinocytes. Autoantibodies (AAbs) targeting these molecules ultimately lead to the blister formation characteristic of pemphigus vulgaris (PV) or pemphigus foliaceus (PF). To investigate the molecular events following autoantibody binding up to 48 hours, we quantified transcriptome and proteome dynamics during split formation in a human skin organ culture (HSOC) model for PV and in 2D cell-culture model for PV and endemic PF. Treatment of the cells in 2D culture with PX43, a single-chain variable fragment targeting DSG1/3 or with endemic PF anti-DSG1 IgG yielded neither a significant transcriptome nor a proteome response over time relative to the respective IgG controls. When treating the HSOC model with mouse antibody AK23 (targeting DSG3) or with PX43, only the latter induced split formation. In the absence of split formation, no differentially regulated pathways were detected at the transcriptomic level. Split formation, observed as early as 5 hours post-injection, was associated with significant and sustained upregulation of IFNγ and TNFα related genes, mediated by upstream NFκB, MAPK, and JAK-STAT pathways. The gene expression changes, corroborated by proteomics data, were strongly correlated with early wounding and keratinocyte detachment, as well as the transcriptome profile in the skin from PV patients, while inversely associated with keratinocyte differentiation and cell stretching. The co-occurrence of well-wide and long-lasting transcriptome and proteome responses with split formation suggests a multistep process in pemphigus. Thereby desmosome weakening/remodelling is the first step following autoantibody binding, which leads to a biomechanical changes and initial split formation. This triggers a stress response in keratinocytes which is characterized by inflammatory gene expression. This new, multistep process of pemphigus pathogenesis points to several potential therapeutic strategies to treat the disorder, e.g., maintaining desmosome stability or targeting the inflammatory signature.Competing Interest StatementThe authors have declared no competing interest.Footnotes* https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE285010
ISSN:	2692-8205
DOI:	10.1101/2025.02.10.637416
Fuente:	Biological Science Database