Structure and Function of Hemidesmosomes: More Than Simple Adhesion Complexes
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View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector Structure and Function of Hemidesmosomes: More Than Simple Adhesion Complexes Luca Borradori and Arnoud Sonnenberg* Department of Dermatology, DHURDV, University Hospital of Geneva, Geneva, Switzerland; *Division of Cell Biology, The Netherlands Cancer Institute, Amsterdam, The Netherlands The attachment of cells to the extracellular matrix is clear that the α6β4 integrin, a major component of of crucial importance in the maintenance of tissue hemidesmosomes, is able to transduce signals from structure and integrity. In stratified epithelia such as in the extracellular matrix to the interior of the cell, that skin as well as in other complex epithelia multiprotein critically modulate the organization of the cyto- complexes called hemidesmosomes are involved in skeleton, proliferation, apoptosis, and differentiation. promoting the adhesion of epithelial cells to the under- Nevertheless, our knowledge of the mechanisms regu- lying basement membrane. In the past few years our lating the functional state of hemidesmosomes and, understanding of the role of hemidesmosomes has hence, the dynamics of cell adhesion, a process of crucial importance in development, wound healing improved considerably. Their importance has become or tumor invasion, remains limited. The aims of apparent in clinical conditions, in which absence or this review are to highlight the recent progresses of defects of hemidesmosomal proteins result in devastat- our knowledge on the organization and assembly ing blistering diseases of the skin. Molecular genetic of hemidesmosomes, their involvement in signaling studies have increased our knowledge of the function pathways as well as their participation in clinical of the various components of hemidesmosomes and pathologic conditions. Key words: bullous pemphigoid enabled the characterization of protein–protein inter- antigens signalling/cell adhesion/epidermolysis bullosa/inte- actions involved in their assembly. It has become grins. J Invest Dermatol 112:411–418, 1999 emidesmosomes (HD) are specialized junctional of HD. There is accumulating evidence which indicates that complexes, that contribute to the attachment of different factors, such as extracellular matrix (ECM) proteins and epithelial cells to the underlying basement mem- growth factors, regulate their function (Giancotti, 1996). The α6β4 brane in stratified and other complex epithelia, integrin appears to act as a regulatory component by transducing such as the skin, the cornea, parts of the gastrointes- signals that profoundly affect the entire cellular machinery (Mainiero Htinal and respiratory tract, and the amnion. These multiprotein et al, 1995, 1996, 1997). Hence, HD may not only represent complexes determine cell–stromal coherence and provide cells with structural adhesion complexes, but they may also serve via the cues critical for their polarization, their spatial organization, and α6β4 integrin as ‘‘signaling devices’’ affecting the cell phenotype. for tissue architecture (Borradori and Sonnenberg, 1996; Green The aim of this review is to summarize recent developments in and Jones, 1996; Gumbiner, 1996). Although these structures our understanding of the molecular organization of HD. Clinical appear relatively stable, which would counteract cell migration and observations as well as cell biologic studies, including gene targeting displacement, their functional activity can be modulated. The experiments, transfection, and yeast two-hybrid system analyses, regulation of the adhesive interactions of HD with the underlying have dramatically increased our knowledge of the function of basement membrane is essential in various normal biologic processes, the various hemidesmosomal constituents and allowed defining such as wound healing and tissue morphogenesis. The importance functionally important domains within these proteins. of these complexes is attested by the fact that an altered expression of hemidesmosomal constituents results in several types of blistering MORPHOLOGY AND MOLECULAR ORGANIZATION disorders of the skin (Table I) (Christiano and Uitto, 1996) and is OF HEMIDESMOSOMES likely involved in the development and progression of certain cancers (Rabinovitz and Mercurio, 1996). Considerable progress Ultrastructurally, HD appear as small electron dense domains (less has been made in defining the molecular structure and architecture than 0.5 µm) of the plasma membrane on the ventral surface of basal keratinocytes of human skin. Their most conspicuous component is a tripartite cytoplasmic plaque, to which the bundles of intermediate filaments (IF) are attached (Fig 1). HD are associated Manuscript received November 9, 1998; revised December 9, 1998; with a sub-basal dense plate in the lamina lucida and are connected accepted for publication December 14, 1998. Reprint requests to: Luca Borradori, Clinique de Dermatologie, Hoˆpital via fine thread-like anchoring filaments to the lamina densa. In its Cantonal Universitaire, Rue Micheli du Crest 26, CH-1211 Gene`ve, turn, the latter seems to be anchored to the underlying papillary Switzerland. dermis by the cross-banded anchoring fibrils. These various mor- Abbreviations: BP180, bullous pemphigoid antigen 180; BP230, bullous phological structures, i.e., IF, hemidesmosomal plaque, anchoring pemphigoid antigen 230; HD, hemidesmosome. filaments, and anchoring fibrils, constitute a functional unit named 0022-202X/99/$10.50 · Copyright © 1999 by The Society for Investigative Dermatology, Inc. 411 412 BORRADORI AND SONNENBERG THE JOURNAL OF INVESTIGATIVE DERMATOLOGY Table I. Molecular constituents of hemidesmosomes and functionally associated structures and their involvement in human diseases (see text for references) Structural element Protein Knockout animal model Diseasea Autoimmune Inherited Intermediate filaments Keratins 5 and 14 Yes – EBS Hemidesmosomes BP230 (BPAG1) Yes Bullous pemphigoid – Hemidesmosomes Plectin Yes Pemphigoid-like disease(?) EBS-MD Hemidesmosomes α6 integrin subunit Yes – JEB-PA β4 integrin subunit Yes Cicatricial pemphigoid(?) JEB-PA Hemidesmosomes— BP180 (BPAG2) No Bullous pemphigoid GABEB Anchoring filaments Cicatricial pemphigoid Gestational pemphigoid Anchoring filaments Laminin-5 (α3β3γ2) Yes (α3,β3b) Cicatricial pemphigoid JEB GABEB Anchoring filaments LAD-1c No LABD GABEBd Anchoring fibrils Type VII collagen Yese EBA DEB Bullous SLE aAutoimmune blistering diseases are associated with autoantibodies directed against constituents of the hemidesmosomal adhesion complex, while mutations in their genes result in inherited bullous disorders with often a similar phenotype. In autoimmune blistering diseases autoantibodies might be directed against additional target antigens. EBS, epidermolysis bullosa simplex; MD, muscular dystrophy; GABEB, generalized atrophic benign epidermolysis bullosa; JEB, junctional epidermolysis bullosa; PA, pyloric atresia; DEB, dystrophic epidermolysis bullosa; LABD, linear IgA bullous dermatosis; SLE, systemic lupus erythematosus. bA spontaneous mutation in the murine β3 gene resulting in a JEB phenotype has been described (Kuster et al, 1997). cLAD-1, the linear IgA bullous dermatosis antigen 1, might represent a proteolytic product of BP180 encompassing its extracellular domain. dLack of immunoreactivity in patients’ skin. eUitto J et al, 1988 (personal communication). THE HEMIDESMOSOMAL PLAQUE COMPONENTS BP230 AND PLECTIN CONNECT THE INTERMEDIATE FILAMENTS CYTOSKELETON TO THE PLASMA MEMBRANE The cytoplasmic plaque constituents include the bullous pemphig- oid antigen 230 (BP230, also named bullous pemphigoid antigen 1) (Stanley et al, 1988; Sawamura et al, 1991), plectin (Wiche et al, 1991; McLean et al, 1996), and other less well characterized proteins, the two high molecular weight proteins called HD1 (Hieda et al, 1992) and IFAP 300 (Skalli et al, 1994), and the protein P200 (Kurpakus and Jones, 1991). BP230 and plectin are proteins with related sequences belonging to the plakin family of proteins implicated in the organization of the cytoskeletal architecture (Tanaka et al, 1991; Ruhrberg and Figure 1. Electron microscopy study showing the basal cell surface Watt, 1997) (Fig 2). Based on their primary sequence, they are of a human keratinocyte with hemidesmosomes (HD) and the dermo–epidermal junction. The most conspicuous structural component predicted to contain a central coil-coiled domain flanked by two of HD is an electron-dense triangular shaped cytoplasmic plaque (HD), to globular domains. BP230 was first recognized as a target antigen which bundles of keratin intermediate filament (IF) insert. Extracellularly, in bullous pemphigoid, which is an autoimmune blistering disorder HD display a sub-basal dense plate that runs parallel to the plasma membrane of the skin (Stanley et al, 1981). Its COOH-terminal domain has (arrowhead). Thin thread-like structures named anchoring filaments (AF) the ability to associate with IF, implying a role of this protein in transverse the electron-lucent lamina lucida (LL) and appear to connect the attachment of the keratin IF to the hemidesmosomal plaque the cytoplasmic plaque to the lamina densa (LD). In the dermis, closely (Yang et al, 1996). In addition, transfection studies and yeast two- associated with the lamina densa are cross-banded anchoring fibrils (AFb) hybrid analyses have provided evidence that indicates that the and in the lower dermis collagen fibres (Col). Scale bar: 100 nm (electron