RESUMEN
The role of desmosomal cadherin desmocollin-2 (Dsc2) in regulating barrier function in intestinal epithelial cells (IECs) is not well understood. Here, we report the consequences of silencing Dsc2 on IEC barrier function in vivo using mice with inducible intestinal-epithelial-specific Dsc2 knockdown (KD) (Dsc2ERΔIEC). While the small intestinal gross architecture was maintained, loss of epithelial Dsc2 influenced desmosomal plaque structure, which was smaller in size and had increased intermembrane space between adjacent epithelial cells. Functional analysis revealed that loss of Dsc2 increased intestinal permeability in vivo, supporting a role for Dsc2 in the regulation of intestinal epithelial barrier function. These results were corroborated in model human IECs in which Dsc2 KD resulted in decreased cell-cell adhesion and impaired barrier function. It is noteworthy that Dsc2 KD cells exhibited delayed recruitment of desmoglein-2 (Dsg2) to the plasma membrane after calcium switch-induced intercellular junction reassembly, while E-cadherin accumulation was unaffected. Mechanistically, loss of Dsc2 increased desmoplakin (DP I/II) protein expression and promoted intermediate filament interaction with DP I/II and was associated with enhanced tension on desmosomes as measured by a Dsg2-tension sensor. In conclusion, we provide new insights on Dsc2 regulation of mechanical tension, adhesion, and barrier function in IECs.
Asunto(s)
Adhesión Celular/fisiología , Desmocolinas/metabolismo , Animales , Cadherinas/metabolismo , Línea Celular , Membrana Celular/metabolismo , Desmocolinas/genética , Desmocolinas/fisiología , Desmogleína 2/metabolismo , Cadherinas Desmosómicas/metabolismo , Cadherinas Desmosómicas/fisiología , Desmosomas/metabolismo , Humanos , Uniones Intercelulares/metabolismo , Mucosa Intestinal , Masculino , Ratones , Ratones NoqueadosRESUMEN
Pseudoporphyria refers to a rare bullous dermatosis characterized by the clinical and histological features of porfiria cutanea tarda without abnormalities in porphyrin metabolism. The pathogenesis is heterogeneous and several exogenous factors may promote the bullous lesion formation, including medications, end stage renal disease, dialysis and tanning beds. Regarding treatment of this condition, in literature different therapy have been reported, such as glutathione and his precursor N-acetylcysteine, which presents anti-oxidant properties; however even more toxic drugs, such as chloroquine, are used. Moreover, in patients with drug-induced PP discontinuation of the offending agent, if possible, is a crucial aspect of the clinical management. We report two cases of dialysis patients presenting blisters on extremities, which healed with the avoidance of UV exposure and oral Vitamin D supplementation. Interestingly Vitamin D despite the lack of antioxidant properties led to a completely resolution of PP in both our patients within 30 days. A possible explanation of this finding is that Vitamin D, playing a key role in the regulation of serum Ca2+, can modulated cadherin-cadherin interactions and led to healing of pseudoporphyria bullous lesions. Finally we highlight the prominent role of UV-exposure in PP elicitation thus a good photoprotection is essential for all patients with pseudoporphyria.
Asunto(s)
Trastornos por Fotosensibilidad/tratamiento farmacológico , Diálisis Renal/efectos adversos , Enfermedades Cutáneas Vesiculoampollosas/tratamiento farmacológico , Luz Solar/efectos adversos , Rayos Ultravioleta/efectos adversos , Deficiencia de Vitamina D/complicaciones , Vitamina D/uso terapéutico , Anciano , Calcio/fisiología , Técnicas Cosméticas/efectos adversos , Cadherinas Desmosómicas/fisiología , Diagnóstico Diferencial , Femenino , Humanos , Uniones Intercelulares , Fallo Renal Crónico/complicaciones , Fallo Renal Crónico/terapia , Persona de Mediana Edad , Nefroesclerosis/complicaciones , Diálisis Peritoneal/efectos adversos , Trastornos por Fotosensibilidad/diagnóstico , Trastornos por Fotosensibilidad/etiología , Porfiria Cutánea Tardía/diagnóstico , Porfirinas/análisis , Enfermedades Cutáneas Vesiculoampollosas/diagnóstico , Enfermedades Cutáneas Vesiculoampollosas/etiología , Vitamina D/fisiología , Deficiencia de Vitamina D/tratamiento farmacológicoRESUMEN
Cell-cell connectivity is an absolute requirement for the correct functioning of cells, tissues and entire organisms. At the level of the individual cell, direct cell-cell adherence and communication is mediated by the intercellular junction complexes: desmosomes, adherens, tight and gap junctions. A broad spectrum of inherited, infectious and auto-immune diseases can affect the proper function of intercellular junctions and result in either diseases affecting specific individual tissues or widespread syndromic conditions. A particularly diverse group of diseases result from direct or indirect disruption of desmosomes--a consequence of their importance in tissue integrity, their extensive distribution, complex structure, and the wide variety of functions their components accomplish. As a consequence, disruption of desmosomal assembly, structure or integrity disrupts not only their intercellular adhesive function but also their functions in cell communication and regulation, leading to such diverse pathologies as cardiomyopathy, epidermal and mucosal blistering, palmoplantar keratoderma, woolly hair, keratosis, epidermolysis bullosa, ectodermal dysplasia and alopecia. Here, as well as describing the importance of the other intercellular junctions, we focus primarily on the desmosome, its structure and its role in disease. We will examine the various pathologies that result from impairment of desmosome function and thereby demonstrate the importance of desmosomes to tissues and to the organism as a whole.
Asunto(s)
Adhesión Celular/fisiología , Comunicación Celular/fisiología , Desmosomas/fisiología , Enfermedad/etiología , Proteínas del Dominio Armadillo/metabolismo , Proteínas del Dominio Armadillo/fisiología , Enfermedades Autoinmunes/etiología , Calcio/metabolismo , Cistatina A/fisiología , Cadherinas Desmosómicas/metabolismo , Cadherinas Desmosómicas/fisiología , Desmosomas/química , Humanos , Infecciones/etiología , Mutación/genética , Neoplasias/etiología , Plaquinas/metabolismo , Plaquinas/fisiología , Enfermedades de la Piel/etiologíaRESUMEN
Desmoglein 1 (Dsg1) is a desmosomal cadherin that is essential to epidermal integrity. In the blistering diseases bullous impetigo and staphylococcal scalded-skin syndrome, pathogenesis depends on cleavage of Dsg1 by a bacterial protease, exfoliative toxin A, which removes residues 1 to 381 of the Dsg1 ectodomain. However, the cellular responses to Dsg1 cleavage that precipitate keratinocyte separation to induce blister formation are unknown. Here, we show that ectodomain-deleted Dsg1 (Δ381-Dsg1) mimics the toxin-cleaved cadherin, disrupts desmosomes, and reduces the mechanical integrity of keratinocyte sheets. In addition, we demonstrate that truncated Dsg1 remains associated with its catenin partner, plakoglobin, and causes a reduction in the levels of endogenous desmosomal cadherins in a dose-dependent manner, leading us to hypothesize that plakoglobin sequestration by truncated Dsg1 destabilizes other cadherins. Accordingly, a triple-point mutant of the ectodomain-deleted cadherin, which is uncoupled from plakoglobin, does not impair adhesion, indicating that this interaction is essential to the pathogenic potential of truncated Dsg1. Moreover, we demonstrate that increasing plakoglobin levels rescues cadherin expression, desmosome organization, and functional adhesion in cells expressing Δ381-Dsg1 or treated with exfoliative toxin A. Finally, we report that histone deacetylase inhibition up-regulates desmosomal cadherins and prevents the loss of adhesion induced by Dsg1 truncation. These findings further our understanding of the mechanism of exfoliative toxin-induced pathology and suggest novel strategies to suppress blistering in bulbous impetigo and staphylococcal scalded-skin syndrome.
Asunto(s)
Vesícula/etiología , Dermatitis Exfoliativa/etiología , Desmogleína 1/genética , Exfoliatinas/efectos adversos , Dominios y Motivos de Interacción de Proteínas/genética , Eliminación de Secuencia/fisiología , gamma Catenina/fisiología , Vesícula/genética , Vesícula/patología , Adhesión Celular/genética , Células Cultivadas , Dermatitis Exfoliativa/genética , Dermatitis Exfoliativa/patología , Desmogleína 1/química , Desmogleína 1/metabolismo , Desmogleína 1/fisiología , Cadherinas Desmosómicas/química , Cadherinas Desmosómicas/genética , Cadherinas Desmosómicas/metabolismo , Cadherinas Desmosómicas/fisiología , Exfoliatinas/farmacología , Humanos , Queratinocitos/efectos de los fármacos , Queratinocitos/metabolismo , Queratinocitos/patología , Queratinocitos/fisiología , Dominios y Motivos de Interacción de Proteínas/fisiología , Procesamiento Proteico-Postraduccional/efectos de los fármacos , Piel/metabolismo , Piel/patología , Infecciones Cutáneas Estafilocócicas/genética , Infecciones Cutáneas Estafilocócicas/metabolismo , Infecciones Cutáneas Estafilocócicas/patología , Transducción Genética , gamma Catenina/genética , gamma Catenina/metabolismoRESUMEN
Desmosomes are intercellular junctions of epithelia and cardiac muscle. They resist mechanical stress because they adopt a strongly adhesive state in which they are said to be hyper-adhesive and which distinguishes them from other intercellular junctions; desmosomes are specialised for strong adhesion and their failure can result in diseases of the skin and heart. They are also dynamic structures whose adhesiveness can switch between high and low affinity adhesive states during processes such as embryonic development and wound healing, the switching being signalled by protein kinase C. Desmosomes may also act as signalling centres, regulating the availability of signalling molecules and thereby participating in fundamental processes such as cell proliferation, differentiation and morphogenesis. Here we consider the structure, composition and function of desmosomes, and their role in embryonic development and disease.
Asunto(s)
Desmosomas/química , Desmosomas/fisiología , Adhesividad , Animales , Proteínas del Dominio Armadillo/fisiología , Fenómenos Biomecánicos , Adhesión Celular , Desmoplaquinas/fisiología , Cadherinas Desmosómicas/fisiología , Desmosomas/ultraestructura , Desarrollo Embrionario , Células Epiteliales/fisiología , Células Epiteliales/ultraestructura , Humanos , Filamentos Intermedios/fisiología , Proteínas de la Membrana/fisiología , Modelos Biológicos , Morfogénesis , Transducción de Señal , Estrés MecánicoRESUMEN
Desmosomes are highly specialized anchoring junctions that link intermediate filaments to sites of intercellular adhesion, thus facilitating the formation of a supracellular scaffolding that distributes mechanical forces throughout a tissue. These junctions are thus particularly important for maintaining the integrity of tissues that endure physical stress, such as the epidermis and myocardium. The importance of the classic mechanical functions of desmosomal constituents is underscored by pathologies reported in animal models and an ever-expanding list of human mutations that target both desmosomal cadherins and their associated cytoskeletal anchoring proteins. However, the notion that desmosomes are static structures that exist simply to glue cells together belies their susceptibility to remodeling in response to environmental cues and their important tissue-specific roles in cell behavior and signaling. Here, we review the molecular blueprint of the desmosome and models for assembling its protein components to form an adhesive interface and the desmosomal plaque. We also discuss emerging evidence of supra-adhesive roles for desmosomal proteins in regulating tissue morphogenesis and homeostasis. Finally, we highlight the dynamic nature of these adhesive organelles, examining mechanisms in health and disease for modulating adhesive strength and stability of desmosomes.
Asunto(s)
Desmosomas/fisiología , Filamentos Intermedios/fisiología , Queratinocitos/citología , Animales , Adhesión Celular/fisiología , Proteínas del Citoesqueleto/fisiología , Cadherinas Desmosómicas/fisiología , Desmosomas/ultraestructura , Humanos , Filamentos Intermedios/ultraestructura , Queratinocitos/fisiología , Queratinocitos/ultraestructura , Modelos AnimalesRESUMEN
The desmosomal cadherins, which include desmogleins and desmocollins, are Ca(2+)-dependent adhesion molecules that cooperate to make up the adhesive core of intercellular junctions known as desmosomes. The roles of desmosomal cadherins in epidermal integrity and as targets in human cutaneous disease have been well established. However, the molecular basis of these disorders is still poorly understood, due in part to a lack of fundamental knowledge about the organization of the adhesive interface and molecular machinery that dictates the proper presentation of desmogleins and desmocollins on the cell surface. Further, the diversity of the desmosomal cadherin family, and their individualized expression patterns within complex tissues, suggests that these adhesion molecules may have differentiation-specific functions that transcend their roles in intercellular adhesion. Here we will review the most recent data from our own group and others that are beginning to unveil the diverse properties and functions of this complex family of adhesion molecules.