Meeting report – Alpine desmosome disease meeting 2024: advances and emerging topics in desmosomes and related diseases

Desmosomes are adhesive cell contacts which mechanically reinforce and maintain proper intercellular adhesion and are required for tissue integrity and homeostasis. During the past few decades, desmosomes have come into focus in cell adhesion research owing to significant advances in understanding the regulation of desmosome turnover and their interplay with adherens junctions (AJs) (Bharathan et al., 2024). All desmosomes share a common molecular blueprint (Fig. 1). The core of the desmosome comprises different isoforms of cadherin-type adhesion molecules of the desmoglein (Dsg) and desmocollin (Dsc) subfamilies. In the desmosomal plaque, Dsg and Dsc are organized by the armadillo family members plakoglobin (Pg) and plakophilin (Pkp) and are anchored via desmoplakin (Dp) to the intermediate filament (IF) cytoskeleton (Perl et al., 2024). The process of coupling and uncoupling of desmosomes to intermediate filaments, at least in keratinocytes, is a dynamic process regulated by phosphorylation of Pg and Dp in antagonistic manner (Vielmuth et al., 2023).

In stratified epithelia, desmosomes are present as individual cell contacts that exhibit bidirectional crosstalk with AJs to allow cells to adapt to environmental mechanical cues (Nanavati et al., 2024). In contrast, in simple barrier-forming epithelia, such as in the gut lumen, desmosomes are associated with tight junctions (TJs) and AJs to form an organized junctional complex (Schlegel et al., 2021). Finally, in the myocardium – the tissue most constantly exposed to mechanical stress – desmosomes and AJs in intercalated discs (ICDs) are intermingled to form complex adhesive junctions. These regions, termed areae compositae, represent assemblies of desmosomes and AJs with gap junctions (GJs) and Na⁺ and Ca²⁺ channels, which together form the connexome (Agullo-Pascual et al., 2013; Nielsen et al., 2023; Yeruva and Waschke, 2023).

Desmosome dysfunction can be caused by genetic variants encoding defective desmosomal components, autoantibodies targeting desmosomal cadherins and inflammatory processes impairing desmosome turnover, leading to a variety of desmosome-associated diseases (Fig. 2) (Hegazy et al., 2022; Spindler et al., 2023). Pemphigus, in which autoantibodies impair desmosome-mediated cell adhesion resulting in formation of blisters and erosions in the epidermis and mucous membranes, is a model disease for desmosome dysfunction (Egami et al., 2020). Desmosome formation and regulation is also compromised in other blistering skin disorders, such as Darier disease (DD) and Hailey–Hailey disease (Harmon et al., 2024). The pathogenesis of arrhythmogenic cardiomyopathy (ACM) is more complex and primarily involves cardiomyocyte dysfunction due to mutations in desmosomal ICD components. ACM can be exacerbated by physical exercise or inflammatory processes (Gasperetti et al., 2021). In inflammatory bowel diseases (IBD), immune cell dysregulation and epithelial cell death lead to a vicious cycle (Patankar and Becker, 2020) that compromises gut barrier integrity in a process that alters desmosome ultrastructure and function (Toivola et al., 2015).

The Alpine Desmosome Disease Meeting (https://desmosome-disease-meeting.com/) was held for the second time on October 9–11, 2024 in Grainau, Germany and was organized by Volker Spindler (University Medical Center Hamburg-Eppendorf) and Jens Waschke (Ludwig-Maximilians University Munich). This meeting fosters interactions between basic scientists and clinical researchers from different fields to discuss recent advances in desmosome structure and function as well as insights into disease pathogenesis and new treatment approaches. In total, 70 scientists from all career stages attended the 2-day symposium, which was again held at the beautiful and remote Eibsee in Grainau. The meeting was structured in four sessions on the ‘basic biology of desmosomes’, ‘arrhythmogenic cardiomyopathy’, ‘pemphigus’ and ‘IBD and other diseases’ and included talks from 17 established researchers combined with short talks selected from submitted abstracts, the latter of which were also presented during a poster session. In this meeting report, we summarize the advances in the field since the last symposium (Spindler et al., 2023) and describe hot topics discussed in the talks.

To start the symposium, Kathy Green (Northwestern University) reviewed the importance of the appearance of desmosomes late in evolution, which allowed for increasingly complex tissues to maintain their mechanical integrity while also providing opportunities for the formation of epithelial barriers with novel functions (Green et al., 2020). These emergent properties of epithelial tissues include new mechanical properties conferred by physical and functional integration of the IF–desmosome network with the more ancient actin contractile system. For example, by governing the recruitment and distribution of Arp2/3-dependent actin remodeling machinery in cells, the desmosomal cadherin Dsg1 controls both the process of delamination (i.e. the transition of keratinocytes to the spinous layer during differentiation) (Nekrasova et al., 2018) and keratinocyte-autonomous anti-inflammatory functions to allow proper skin development and homeostasis. The Green lab identified potential adapter proteins that couple Dsg1 with Arp2/3 machinery, an association that is required for both delamination and the ability to suppress Th17 inflammatory signaling pathways in vitro, pathways that were also observed to be modulated in Dsg1-deficient mice (Godsel et al., 2022). A new analysis of Dsg1-deficient mice to identify cytoskeletal and proliferative signaling pathways that help explain how the epidermis overcomes early defects in stratification due to Dsg1 loss was also presented.

Andrew Kowalczyk (The Pennsylvania State University) presented a series of imaging studies revealing associations between adhesive intercellular junctions and the endoplasmic reticulum (ER). Previous work from the group has demonstrated that peripheral ER tubules associate with keratin filaments and the desmosome plaque (Bharathan et al., 2023). Emerging studies from the group are identifying AJs as key regulators of ER recruitment to the cell periphery and as modulators of ER contacts with the plasma membrane adjacent to desmosomes. These studies are also informing potential pathomechanisms of DD, a rare acantholytic disorder with impaired keratinocyte coherence caused by heterozygous mutations in the sarcoplasmic/endoplasmic reticulum Ca²⁺ ATPase 2 (SERCA2) ER Ca²⁺ pump. The coordinated architectural arrangement of ER and cell–cell junctions suggest that local regulation of cytosolic Ca²⁺ and plasma membrane lipids by the ER might be perturbed in DD keratinocytes, leading to desmosome dysfunction. Studies from the Green lab suggest that DD cells are sensitive to age-related stressors, such as oxidative damage, which result in modifications detrimental to the IF–desmosome scaffold. Interestingly, the Green lab reports that DD cells and tissues also exhibit altered actin signaling pathways, highlighting another example of the interconnected nature of actin, IF and associated junctional complexes (Roth-Carter et al., 2023). The structural integration of cytoplasmic organelles, the keratin IF network and adhesive junctions might underly the alterations in metabolic pathways and adhesion observed in DD and in other desmosome-related disorders. Adding to the emergent concept that desmosomes in different tissues are structurally and functionally linked to different organelles, Mario Delmar (New York University) presented data showing that Pkp2 deficiency impairs the anchoring of desmin to the nuclear envelope and disrupts nuclear envelope integrity, leading to consequent DNA damage (Perez-Hernandez et al., 2022). Furthermore, Christoph Becker (Friedrich-Alexander University Erlangen-Nürnberg) emphasized the critical role of mitochondria in regulating epithelial cell death and barrier functions, and presented data suggesting that dysregulated mitochondrial dynamics are a driver of IBD pathophysiology.

A short historical perspective on desmosome research by David Garrod (University of Manchester) was followed by a review of desmosomal hyper-adhesion (Garrod, 2010). Immature desmosomes are Ca²⁺ dependent, but upon maturation they become Ca²⁺-independent – hence, immature and mature desmosomes are susceptible or resistant to chelation of extracellular Ca²⁺, respectively. Live-cell imaging has shown that desmosomes become more stable with hyper-adhesion (Fülle et al., 2021). Moreover, desmosomes consist of two contrasting protein moieties (desmosome dualism). One moiety is very stable and comprises the desmosomal cadherins Pg and Dp; the other, consisting of Pkp2, is highly mobile. Wound epithelium and some tumors show internalization of whole desmosomes. In growth factor-induced scattering of simple epithelial cells, loss of cell–cell contact involved internalization of whole desmosomes, which retain a stable moiety and highly mobile Pkp2. No evidence for desmosome disassembly was observed. Protein proximity mapping using biotinylation of Ca²⁺-dependent and hyper-adhesive desmosomes, with Dsc2a, plakoglobin and Pkp2a as baits, showed that the desmosome ‘proximitome’ changes substantially as desmosomes mature (Fülle et al., 2024). The data suggest that individual desmosomal proteins have distinct roles in connecting to cellular signaling pathways and provide further support for the concept of desmosome dualism, in which the properties of Pkp2 differ from those of the more stable proteins.

Carien Niessen (University of Cologne) presented unpublished data that identified a crucial role for AJ in sensing actomyosin contractile forces to mechanically strengthen AJ-actin interactions, providing sufficient counterforce to maintain close proximity of intercellular membranes necessary for desmosome assembly. Moreover, together with the lab of Chen Luxenburg (Tel Aviv University), the Niessen lab showed that in keratinocytes of the epidermis, the spectrin cytoskeleton controls actomyosin organization and tension states important for epidermal barrier function. The data suggest that spectrin regulates desmosomal adhesive strength and cell shape transitions in the epidermis to guide differentiation. Together, these observations with those from the Green and Kowalczyk laboratories indicate how the dynamic and extensive crosstalk between AJ, desmosomes and their associated cytoskeletons regulate epithelial cell functions. Along the same line, Sanjeevi Sivasankar (University of California Davis) presented unpublished data demonstrating that, in human breast cancer MCF7 cells, actomyosin forces induce a conformational change in the N-terminal region of Dp (Dong et al., 2024 preprint). Using super-resolution fluorescence microscopy, biochemical assays and atomistic computer simulations, he showed that actomyosin forces directed to Dp along keratin-19 filaments induce a conformational change in the N-terminal plakin domain of Dp, converting this domain from a folded to an extended conformation. The data suggested that Dp is mechanosensitive and undergoes force-induced conformational changes that enhance the mechanical resilience of desmosomes. These findings are in line with other data presented at the meeting showing that Dsg3 is under tension in a RhoA-dependent manner and that tension is released upon incubation with pemphigus autoantibodies (Jin et al., 2024 preprint).

Volker Spindler presented recent findings from several screening approaches that identified novel modulators of desmosomal adhesion. For example, Krueppel-like factor 5 (KLF5) was identified as a transcriptional regulator of DSG3 expression, a mechanism which is impaired in pemphigus and may be targeted therapeutically (Franz et al., 2024). Additionally, the serine protease inhibitor SERPINB5 modulates desmosome function and epidermal homeostasis on the posttranslational level by affecting the phosphorylation and correct localization of Dp (Rathod et al., 2024). New data were shown that suggest interference with Dp function might result in pleiotropic effects even in tissues not expressing desmosomal molecules.

Masayuki Amagai (Keio University) and Michael Hertl (Philipps University Marburg) described the clinical phenotypes and the standard diagnostic algorithm for pemphigus (Didona et al., 2019; Joly et al., 2020). Specifically, the regulatory network of pro- and anti-inflammatory T and B cells that lead to the generation of presumably short-lived, autoantibody-producing plasma cells is quite well-understood. The impact of the type 2 and type 17 T cell-dominated pro-inflammatory milieu in pemphigus skin lesions is also increasingly understood (Pollmann et al., 2018; Schinner et al., 2023).

Franziska Vielmuth (Ludwig-Maximilians University Munich) summarized that direct inhibition of homo- and heterophilic Dsg binding, together with signaling events attributed at least in part to a specific autoantigen, are the pathogenic mechanisms leading to loss of keratinocyte cell adhesion and blister formation in pemphigus (Ishii et al., 2024, 2020; Schmitt and Waschke, 2021). A new perspective was presented that suggests keratinocytes possess protective features and that autoantibodies in pemphigus induce pro-adhesive rescue mechanisms. To this end, hyper-adhesion protects keratinocytes from pemphigus autoantibody-induced loss of intercellular adhesion (Cirillo et al., 2010; Steinert et al., 2024) and a beneficial upregulation of Dsg2 was reported in vitro and in the skin of pemphigus patients (Miguel et al., 2022; Sigmund et al., 2020). In addition, cyclic AMP (cAMP) signaling was identified as a potential druggable pathway: increased cAMP signaling stabilizes the anchoring of keratin to desmosomes through phosphorylation of Pg at S665 via the cAMP downstream targets PKA and Epac1 (Sigmund et al., 2023; Vielmuth et al., 2023). Apremilast, a phosphodiesterase 4 (PDE4) inhibitor that blocks PDE4-mediated breakdown of cAMP, was reported to be a promising therapeutic agent (Delvaux et al., 2024; Meier et al., 2020; Sigmund et al., 2023).

A clinical view of ACM was introduced by Firat Duru (University of Zurich), who summarized the natural history of the disease as well as the general approach to diagnosis, risk stratification and management. ACM is mainly caused by mutations in genes encoding for desmosome proteins (e.g. PKP2, DSG2/DSC2, JUP, DSP), with resultant fibro-fatty replacement of the myocardium and ventricular tachyarrhythmias (James et al., 2020). ACM is a progressive disease that is among the leading causes of sudden cardiac death (SCD) in adolescents and young athletes. In ACM, different subtypes with right ventricle (RV)-dominant, biventricular and left ventricle (LV)-dominant forms can be distinguished and these subtypes correlate with the affected gene with arrhythmogenic right ventricular cardiomyopathy (ARVC) being the classical and most common form of ACM (James et al., 2020). Clinical diagnosis is often challenging due to genetic variants of unknown significance, incomplete disease penetrance and phenotypic overlaps with other cardiomyopathiess, myocarditis, channelopathies or cardiac sarcoidosis. There is no single diagnostic test that indicates or excludes the presence of overt disease. At the present time, the diagnosis of ACM is established based on modified Task Force Criteria, which provide a widely accepted standard for current clinical research studies across different cohorts (Marcus et al., 2010). It is increasingly recognized that the underlying genotype has a significant impact on the clinical phenotype and natural history of disease, with each affected gene producing different effects. A recent development in the field is the “gene-first” approach, by which ACM is characterized primarily on the basis of underlying pathogenic variants in addition to the clinical phenotype.

Volker Spindler and Camilla Schinner (University Medical Center Hamburg-Eppendorf and University of Bern) highlighted the central role of desmosomal dysfunction in the development of ACM based on a mouse model with abrogated extracellular trans-interactions of DSG2 (DSG2-W2A mutation) (Schinner et al., 2022). Mario Delmar presented data showing that desmosome disruption leads to transcriptional reprogramming, likely through a combination of mechanical and signaling events, both of which are amplified by exercise (Cerrone et al., 2022; Perez-Hernandez et al., 2022; van Opbergen et al., 2022). To compare the pathophysiology of different desmosomal diseases, Jens Waschke summarized findings from different pemphigus and ACM models showing that loss of cell adhesion and dysfunction of signaling mechanisms that regulate cell adhesion are a common feature in their pathogenesis. Similar to in acantholytic epidermis in pemphigus, where the desmosome ultrastructure and keratin anchorage are altered (Egu et al., 2022), Pg-deficient mice show defects in ICD stability (Schinner et al., 2017) and adhesion is impaired in iPSC-derived cardiomyocytes originating from an ACM patient. In line with this, p38 mitogen-activated protein kinase (p38MAPK) and epidermal growth factor receptor (EGFR) activation contribute to loss of cell adhesion in both pemphigus (Egu et al., 2024; Schmitt and Waschke, 2021) and ACM (Shoykhet et al., 2023a,b). Autoantibodies from ACM patients also reduce cardiomyocyte adhesion via p38MAPK (Yeruva et al., 2023). Moreover, pemphigus autoantibodies cause inactivation of Rho-associated protein kinase (ROCK), supporting the view that desmosome adhesion is regulated by the actomyosin contractile machinery.

In her keynote lecture, Asma Nusrat (University of Michigan) gave an overview of the structure of the intestinal epithelial barrier and the role of desmosomal cadherins in this context. Desmosomes between gut epithelial cells contain only two cadherins, Dsg2 and Dsc2, which are organized in cholesterol- and sphingolipid-rich membrane microdomains referred to as lipid rafts that provide functional platforms for regulating adhesion and homeostatic signaling (Nusrat et al., 2000; Stahley et al., 2014). The importance of Dsc2 and Dsg2 in controlling the epithelial barrier is evident from intestinal epithelial-specific knockout mouse models for these respective cadherins (Gross et al., 2018; Raya-Sandino et al., 2021). Dysregulation of junctional homeostatic signaling results in a compromised epithelial barrier, which, coupled with aberrant immune responses, contributes to the pathogenesis of IBD. The important role of the intestinal epithelial barrier in disease development is underscored by the observation of increased intestinal permeability in a subgroup of healthy relatives of IBD patients, even before the onset of symptoms (Katz et al., 1989; Peeters et al., 1997). The recruitment of leukocytes into the mucosa and ensuing epithelial injury creates an environment rich in inflammatory mediators that modulate intercellular adhesion and compromise barrier function, such as tumour necrosis factor alpha (TNFa), interferon gamma (IFNg) and interleukin 1 beta IL1b (Ivanov et al., 2005). Activation of matrix metalloproteases such as MMP9 and ADAM10 by inflammatory cytokines promotes the cleavage of Dsg2. Notably, cleaved cadherin fragments inhibit intercellular adhesion and enhance proliferation via EGFR2 and EGFR3 (HER2/3) signaling as an early wound repair response to mucosal injury (Kamekura et al., 2015; Yulis et al., 2018).

Christoph Becker underscored that the epithelial barrier serves not only as a physical defense but also as a dynamic communication hub, mediating interactions between the gut microbiome and the mucosal immune system. Dysfunction of the gut barrier is a key driver of chronic intestinal inflammation in mouse models (Gunther et al., 2011; Patankar et al., 2021). In inflamed gut, dysregulation of cell death pathways in epithelial cells contributes to barrier disruption and the subsequent development of colitis (Patankar and Becker, 2020). In summary, desmosomal cadherins play an important adhesive and barrier role in simple gut epithelial cells while also facilitating the repair of the inflamed mucosa by promoting collective epithelial cell migration, proliferation, inflammation and wound healing. In this context, Nicolas Schlegel (University Hospital Würzburg) outlined that p38 MAPK and EGFR signaling mediate regulation of enterocyte proliferation and differentiation by Dsg2 (Schlegel et al., 2021). Immunostaining of the intestinal mucosa revealed decreased Dsg2 protein levels and altered desmosome ultrastructure in multiple cohorts of individuals with IBD and active inflammation (Schlegel et al., 2021; Spindler et al., 2015). Finally, a Dsg2-specific antibody that binds to the Dsg2 extracellular domain has been shown to compromise barrier function, mimicking the effects associated with pro-inflammatory cytokines (Schlegel et al., 2010). Unpublished data indicate that in mouse models, loss of desmosomal components, as well as rare variants occurring in individuals with IBD, can induce a dysbalanced immune response (Kugelmann et al., 2024 preprint). Taken together, these studies establish loss of desmosome integrity in several cohorts of individuals with digestive tract inflammation. Because most of these samples were derived from individuals that underwent surgery due to IBD, it remains to be resolved whether desmosome changes are evident in early disease stages or occur later in the inflammatory process.

Inflammation also plays a role in the pathogenesis of ACM. Brenda Gerull (University Hospital Würzburg) reported an early detection of CD11b⁺Ly6G⁻ monocyte/macrophages in hearts of a cardiomyocyte-restricted Pg knockout (Jup KO) mouse model, with shifts towards increased pro-inflammatory or tissue-damaging macrophages within the CD11b⁺Ly6G⁻ subpopulation. To establish an in vivo imaging method to assess myocardial inflammation, they used ¹⁸F-fluordeoxyglucose positron emission tomography ([¹⁸F]FDG-PET), as [¹⁸F]FDG is actively taken up by myeloid cells, such as monocytes, macrophages and dendritic cells. They were able to show increased [¹⁸F]FDG uptake in Pg-deficient hearts compared to that in controls. However, although the [¹⁸F]FDG signal did not directly correlate with macrophage infiltration, it did correlate with a surrogate marker of cardiomyocyte hypertrophy, suggesting local detection of metabolic remodeling in an ongoing disease process.

Currently, desmosome diseases can only be treated symptomatically through modulation of the immune system and depletion of autoantibodies and autoantibody-producing B cells, as well as antiarrhythmic therapies for ACM. Thus, based on the current research characterizing disease pathogenesis, new and more specific therapy approaches should be established to fulfill an unmet medical need to complement established treatment paradigms. During the meeting, a variety of new treatment strategies were presented and discussed.

For ACM, in which pathogenic variants in genes encoding desmosomal components are a main driver, Mario Delmar showed that gene replacement therapy in a murine model of PKP2 deficiency is safe and effective (van Opbergen et al., 2024), thus supporting efforts to implement PKP2 gene replacement therapy in individuals with PKP2-ACM in Phase I clinical trials. For pemphigus, Michael Hertl gave a comprehensive overview of established treatment options as well as new targeted treatment strategies that are currently being or have already been tested. A plethora of B cell-targeted treatment approaches are being developed, ranging from monoclonal antibodies that recognize B cell-specific surface proteins like CD20, to chimeric autoantibody receptor (CAAR)-T cells that lyse autoreactive B cells (Didona et al., 2019). Autoreactive T cells induce and perpetuate autoreactive B cells, leading to autoantibody production; thus, they pose great potential as therapeutic targets. Utilizing a limited set of autoantigenic peptides, the Hertl group, together with Topas Therapeutics, Hamburg, performed a Phase 1 trial with Dsg3 peptide-labeled nanoparticles. In a preclinical mouse model of pemphigus, nanoparticle treatment led to an upregulation of T regulatory (Treg) cells and a decrease of anti-Dsg3 specific IgG. In the subsequent clinical trial with anti-Dsg3 IgG-positive patients, an identical approach demonstrated excellent safety and tolerability. A tendency towards decreased type 17 T cells, induction of Treg cells and reduction of pathogenic autoantibodies was observed when the study drug was applied at lower dose levels. These promising findings support our current view that the active disease stage of pemphigus is associated with type 17 T cell activation, whereas phases of disease resolution with decreased autoantibody concentrations are associated with an increase in anti-inflammatory Treg cells (Didona et al., 2019; Holstein et al., 2021). At the present time, major efforts have been made to detect Dsg3-specific T cells via distinct activation markers utilizing human leukocyte antigen (HLA) class Dsg3 peptide dextramers (fluorescent multimers based on dextran backbones), as well as to characterize their cytokine profile, which will be crucial in further T cell-targeted trials in pemphigus (Didona et al., 2024; Polakova et al., 2022; Wieber et al., 2021).

Masayuki Amagai presented his recent work on the role of Treg in maintaining peripheral immunological tolerance to Dsg3. Peripheral tolerance provides a second layer of immune regulation complementary to central tolerance, which eliminates self-reactive immune cells during their development in the thymus or bone marrow. Peripheral tolerance prevents any self-reactive cells that escape this process from causing harm in the rest of the body. Amagai demonstrated a novel form of peripheral tolerance by showing that Treg cells can effectively constrain OX40 signaling in autoreactive T cells, leading to the peripheral elimination of autoreactive T cells targeting Dsg3 (Iriki et al., 2021). OX40 is an important costimulatory molecule for T cell expansion and survival. This discovery unveils a previously unknown mechanism through which Treg cells uphold immune homeostasis and prevent autoimmune responses and suggests that enhancing the function of Dsg3-specific Treg cells holds promise as a therapeutic strategy for managing autoimmune diseases, including pemphigus. In collaboration with Shimon Sakaguchi, who recently developed a method for generating stable and inducible Treg (siTreg) cells (Mikami et al., 2020), Amagai and his colleagues are advancing an antigen-specific therapeutic approach for pemphigus using siTreg cells.

Based on the findings that loss of cell adhesion is an important feature of the pathogenesis of pemphigus and ACM, peptides that crosslink desmosomal cadherins have been shown to be protective in disease models in vivo and ex vivo (Schinner et al., 2020; Spindler et al., 2013). Jens Waschke and Camilla Schinner presented recent findings and proposed stabilization of cell adhesion as a new treatment paradigm for desmosome diseases. Treatment with apremilast to increase cAMP, as well as erlotinib to inhibit EGFR, was protective in vivo and in ex vivo human epidermis (Egu et al., 2024; Sigmund et al., 2023). Similarly, erlotinib stabilized cell adhesion in cardiomyocytes (Shoykhet et al., 2023a) and, according to unpublished data, also reduced arrhythmia in human and murine ACM models. Camilla Schinner introduced a novel high-throughput 2D adhesion assay used to evaluate an FDA-approved drug library. From the compounds identified as pro-adhesive, glucocorticoids were revealed as a promising class of drugs, showing protective effects in an in vivo ACM mouse model. Finally, Volker Spindler outlined that future treatment concepts for modulating cell adhesion should include strategies to specifically tailor the response to the respective tissue to reduce off-target effects.

In summary, during the ADDM24 meeting, several new and exciting topics were discussed (Fig. 2). First, desmosomes are not only structurally connected to organelles but also exhibit functional crosstalk with ER tubules, mitochondria and the nucleus. These interactions modulate organelle function and contribute to the pathogenesis of desmosome-related diseases. Second, impaired cell adhesion is a common feature of desmosome dysfunction in different tissues and contributes to disease pathogenesis in pemphigus and ACM. Third, desmosome adhesion is modulated by actomyosin contractility, which also influences AJs. Fourth, inflammation is regulated by keratinocytes, enterocytes and cardiomyocytes in a desmosome-dependent manner and contributes to desmosome disease pathogenesis in ACM and IBD. Finally, specific therapy concepts are needed to treat individuals suffering from desmosome-related diseases. New approaches, including gene therapy, reconstitution of immune tolerance and metabolic function and stabilization of cell adhesion, might become feasible in the future. The meeting provided an excellent opportunity to discuss these concepts and was endorsed enthusiastically by all participants as unique in its strong focus on desmosomes and outstanding in terms of both research quality and atmosphere. We plan to hold the next meeting at the same location in October 2026.

The meeting was supported by a grant form the German Research Foundation (Deutsche Forschungsgemeinschaft; WA 2474/16-1) to J.W.