The desmosome and pemphigus

Jens Waschke 0 1 0 J. Waschke (&) Institute of Anatomy and Cell Biology, Julius-Maximilians-University , Koellikerstr. 6, 97070 Wrzburg, Germany 1 J. Waschke Institute of Anatomy and Cell Biology, University of Wrzburg , Koellikerstr. 6, 97070 Wrzburg, Germany Desmosomes are patch-like intercellular adhering junctions (maculae adherentes), which, in concert with the related adherens junctions, provide the mechanical strength to intercellular adhesion. Therefore, it is not surprising that desmosomes are abundant in tissues subjected to signiWcant mechanical stress such as stratiWed epithelia and myocardium. Desmosomal adhesion is based on the Ca2+-dependent, homo- and heterophilic transinteraction of cadherin-type adhesion molecules. Desmosomal cadherins are anchored to the intermediate Wlament cytoskeleton by adaptor proteins of the armadillo and plakin families. Desmosomes are dynamic structures subjected to regulation and are therefore targets of signalling pathways, which control their molecular composition and adhesive properties. Moreover, evidence is emerging that desmosomal components themselves take part in outside-in signalling under physiologic and pathologic conditions. Disturbed desmosomal adhesion contributes to the pathogenesis of a number of diseases such as pemphigus, which is caused by autoantibodies against desmosomal cadherins. Beside pemphigus, desmosome-associated diseases are caused by other mechanisms such as genetic defects or bacterial toxins. Because most of these diseases aVect the skin, desmosomes are interesting not only for cell biologists who are inspired by their complex structure and molecular composition, but also for clinical physicians who are confronted with patients suVering from severe blistering skin diseases such as pemphigus. To develop disease-speciWc therapeutic approaches, more insights into the molecular composition and regulation of desmosomes are required. - Desmosomes are intercellular adhering junctions serving to attach neighbouring cells to each other. They are most numerous in tissues subjected to signiWcant mechanical stress such as the stratiWed squamous epithelia of the skin (Bizzozero 1864) and of mucous membranes (Farquhar and Palade 1963) as well as the myocardium (Fawcett and Selby 1958). Moreover, desmosomes are found in simple epithelia and in non-epithelial cells such as the meningeal cells of the arachnoidea (Gusek 1962) and the follicular dendritic cells of lymph follicles (Swartzendruber 1965). Desmosomes were discovered as cell contacts in the middle of the nineteenth century (Calkins and Setzer 2007). By the means of light microscopy, desmosomes were Wrst described in the epidermis by the Italian pathologist Bizzozero in (1864). In his histology text book, the anatomist Josef SchaVer from Vienna introduced the term desmo some, by combining the greek words desmos (bond) and soma (body) although, to that time, he, like most others in the Weld believed that desmosomes were cytoplasm-Wlled intercellular bridges (SchaVer 1920). It took almost another century until Keith Porter, using electron microscopy, was able to conWrm the basic observation of Bizzozero that desmosomes rather are contacts between adjacent cells and to allow the Wrst description on desmosome ultrastructure (Porter 1956). With these new technical advances at hand, several studies were performed in the following years on the distribution and organization of desmosomes in various tissues. In addition, starting in the 1970s, biochemical approaches and molecular cloning techniques were applied to identify the desmosomal components and to characterize their interactions (Drochmans et al. 1978; Moll et al. 1986; Moll and Franke 1982; Schwarz et al. 1990; Skerrow and Matoltsy 1974). SigniWcant insights into the regulation of desmosomal adhesion also came from the Weld of dermatology since it was demonstrated that autoantibodies in patients suVering from the autoimmune blistering skin diseases pemphigus vulgaris (PV), and pemphigus foliaceus (PF), are directed to Ca2+-sensitive cell surface proteins within desmosomes (Eyre and Stanley 1987, 1988; Jones et al. 1986b; Karpati et al. 1993), which were identiWed as the desmosomal cadherins desmoglein 1 (Dsg 1) and Dsg 3 (Amagai et al. 1991; Koulu et al. 1984). The term pemphigus comes from the greek word pemphix (blister) and is being used in dermatology since 1791 (Schmidt et al. 2000), long before it was found that pemphigus is associated with autoantibodies against keratinocyte surface antigens (Beutner and Jordon 1964) and that these antibodies are suYcient to cause acantholysis, i.e. loss of cellcell adhesion, in human skin in vivo and in vitro (Anhalt et al. 1982; Schiltz and Michel 1976). The Wnal break-through was the Wnding that autoantibodies against the extracellular domains of Dsg 3 and Dsg 1 in PV and in PF are pathogenic (Amagai et al. 1995, 1994a, 1992). Therefore, autoantibodies from pemphigus patients have been used to characterize the mechanisms involved in the regulation of desmosomal adhesion. Except from pemphigus, other diseases in which desmosomal adhesion is altered by mutations or bacterial toxins helped to elucidate the functional role of the diVerent desmosomal components. During the last past several years, a number of comprehensive reviews have been published on both desmosome structure and function (Dusek et al. 2007b; Garrod et al. 2002; Getsios et al. 2004b; Green and Simpson 2007; Holthofer et al. 2007; Kitajima 2002; Kottke et al. 2006; Muller et al. 2008a; Yin and Green 2004) and/or on the mechanisms involved in pemphigus pathogenesis (Amagai 2003; Hashimoto 2003; Lanza et al. 2006; Payne et al. 2004; Sharma et al. 2007; Sitaru and Zillikens 2005; Stanley and Amagai 2006), which indicates that the perspective of the existing model of the desmosome and its role in pemphigus pathogenesis are constantly reshaped. Moreover, because even textbook knowledge such as on the molecular composition of myocardial intercalated discs needs revision (Borrmann et al. 2006; Franke et al. 2006), it becomes obvious that after almost 150 years of desmosome research, our knowledge is still far from complete. This article focuses on the mechanisms regulating desmosomal adhesion, which are compromised in diseases such as pemphigus. The ultrastructure and composition of desmosomes The Wrst detailed analysis of desmosome ultrastructure was provided by Odland (1958). Desmosomes are discoid junctions with a diameter of about 0.20.5 m and are composed of two electron-dense plaques in each of the two cells which are separated by an intercellular cleft of 2430 nm (Figs. 1, 2) (Farquhar and Palade 1963; Odland 1958). Within the plaques, an outer dense plaque can be separated from a less dense inner plaque, the latter of which is linked to loops of intermediate Wlament bundles (Kelly 1966). Desmosomes contain members of at least three protein families. Desmosomal cadherins form the (...truncated)