Cell Communication & Adhesion, 21: 129–140, 2014 © 2014 Informa Healthcare USA, Inc. ISSN: 1541-9061 print / 1543-5180 online DOI: 10.3109/15419061.2014.908854

REVIEW ARTICLE

Insights into Desmosome Biology from Inherited Human Skin Disease and Cardiocutaneous Syndromes Daniela Nitoiu, Sarah L. Etheridge, and David P. Kelsell Centre for Cutaneous Research, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK

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Abstract The importance of desmosomes in tissue homeostasis is highlighted by natural and engineered mutations in desmosomal genes, which compromise the skin or heart and in some instances both. Desmosomal gene mutations account for 45–50% of cases of arrhythmogenic right ventricular cardiomyopathy, and are mutated in an array of other disorders such as striate palmoplantar keratoderma, hypotrichosis with or without skin vesicles and lethal acantholytic epidermolysis bullosa. Recently, we reported loss-of-function mutations in the human ADAM17 gene, encoding for the ‘sheddase’ ADAM17, a transmembrane protein which cleaves extracellular domains of substrate proteins including TNF-α, growth factors and desmoglein (DSG) 2. Patients present with cardiomyopathy and an inflammatory skin and bowel syndrome with defective DSG processing. In contrast, the dominantly inherited tylosis with oesophageal cancer appears to result from gain-of-function in ADAM17 due to increased processing via iRHOM2. This review discusses the heterogeneity of mutations in desmosomes and their regulatory proteins. Keywords: desmosomes, inherited diseases, striate PPK, ARVC, ADAM17, CSTA, exfoliative ichthyosis, tylosis, Darier’s disease, iRHOM2

DESMOSOMES – DYNAMIC ADHESION STRUCTURES IN THE SKIN

domain. The five known desmosomal components are the desmosomal cadherins, represented by desmogleins (DSG1–DSG4) and desmocollins (DSC1–DSC3), the armadillo family members plakoglobin (PG)/ γ-catenin and the plakophilins (PKP1–PKP3), and the plakin linker protein desmoplakin (DSP), which anchors the intermediate keratin filaments. The key role of these proteins in the skin (and heart) is reflected by the spectrum of desmosomal mutations identified, which are associated with monogenic skin diseases with/ without cardiac involvement (Table 1; Brooke et al., 2012a). Furthermore, mutations in the desmosome are a major genetic risk factor for arrhythmogenic right ventricular cardiomyopathy (ARVC); a hereditary disorder of the cardiac muscle characterised by ventricular arrhythmias, cardiac failure, and sudden cardiac death. The range of genetic disorders arising from mutations affecting the desmosomal genes, and indeed within the same gene, highlights the complexity and incomplete understanding of how desmosomal components interrelate with each other and with other compartments in a cell-type and differentiation-dependent manner. To date, more than 850 human mutations have been reported in desmosomal genes (Al-Jassar et al., 2013) leading to disorders such as palmoplantar keratoderma (PPK), woolly hair and ARVC (Norgett et al., 2000; McKoy et al., 2000), non-syndromic striate PPK (SPPK; Armstrong et al., 1999; Rickman et al., 1999) and hypotrichosis (Kljuic et al., 2003a). The next sections

Desmosomes are complex macromolecular structures with a key role in maintaining collateral epidermal integrity. Discovered by Italian pathologist Giulio Bizzozero (1846–1901), desmosomes are expressed in a variety of tissue types exposed to mechanical stress, such as the intestinal mucosa and the epithelial cells of the nephron, but are most abundant in the skin and myocardium (Staehelin, 1974; Kelly, 1966; Holthofer et al., 2007; Farquhar & Palade, 1963). A primary function of desmosomes is the anchoring of cytoskeletal keratin intermediate filaments in the epidermis, desmin intermediate filaments in the heart, and vimentin intermediate filaments in meningeal cells and the follicular dendritic cells of lymph nodes to the cell membrane (Green & Gaudry, 2000). All desmosomes, independent of their distribution, are formed by three main classes of proteins divided into three parallel individual zones, arranged symmetrically on the cytoplasmic faces of the plasma membranes of bordering cells and separated by the extracellular Received 21 March 2014; accepted 24 March 2014. Address correspondence to David Kelsell, Centre for Cutaneous Research, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, 4 Newark Street, London E1 2AT, UK. E-mail: [email protected]

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Table 1. Examples of monogenic human disorders associated with desmosomal mutations. Gene DSP Dominant

Recessive

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JUP Dominant Recessive

PKP1 Recessive PKP2 Dominant Recessive PKP3 No mutations in humans to date DSG1 Recessive DSG2 Dominant Recessive DSG3 No mutations in humans to date DSG4 Recessive DSC1 No mutations in humans to date DSC2 Recessive DSC3 Recessive

Disease

ARVC alone (Rampazzo et al., 2002; Norman, 2005) SPPK (Armstrong et al., 1999) PPK, woolly hair and ARVC (Norgett et al., 2006) SPPK, woolly hair and ARVC (Carvajal syndrome) (Norgett et al., 2000; Alcalai et al., 2003) Skin fragility and woolly hair (SFWHS) (Whittock et al., 2002) Lethal acantholytic epidermolysis bullosa (Jonkman et al., 2005) Naxos-like disease affecting DSPI only (Uzumcu et al., 2006) ARVC alone (Asimaki et al., 2007) Focal and diffuse PPK and woolly hair (Cabral et al., 2010a) ARVC, PPK and total alopecia (Erken et al., 2011) Lethal acantholytic epidermolysis bullosa (Pigors et al., 2011) PPK, woolly hair and ARVC (Naxos disease) (McKoy et al., 2000) Ectodermal dysplasia/skin fragility syndrome and ARVC (McGrath et al., 1997) ARVC alone (Gerull et al., 2004) ARVC alone (Awad et al., 2006b)

SPPK (Rickman et al., 1999) PPK, hypotrychosis and hyper-IgE (EPKHE) (Samuelov et al., 2013) ARVC alone (Pilichou et al., 2006) ARVC alone (Syrris et al., 2007)

Hypotrichosis (Kljuic A et al., 2003a) Monilethrix-like hypotrichosis (Shimomura et al., 2006)

ARVC alone (Syrris et al., 2006; Heuser et al., 2006) ARVC, PPK and woolly hair (Simpson et al., 2009) Hypotrichosis with skin vesicles (Ayub et al., 2009)

Gene names: DSP, desmoplakin; PG, plakoglobin; PKP, plakophilin; DSG, desmoglein; DSC, desmocollin. Clinical description: PPK, palmoplantar keratoderma; SPPK, striate palmoplantar keratoderma; ARVC, arrhythmogenic right ventricular cardiomyopathy.

will focus on individual protein components of the desmosome, their basic biology and disease association. DSP DSP, the most abundant desmosomal protein, plays a key role as the linker between the plasma membrane and the intermediate filament complex (Delva et al., 2009). The protein is predicted to form homodimers through an α-helical coiled-coil rod domain which also interconnects a globular amino-terminus, responsible for binding the arm proteins PG and PKPs, and a carboxyterminus domain, responsible for the attachment of intermediate filaments (Holthofer et al., 2007; Kowalczyk et al., 1994; Bornslaeger et al., 2001; Choi et al., 2002; Yin & Green, 2004). Until recently, only two isoforms of DSP (DSPI and DSPII) have been

known. DSPI and DSPII isoforms are produced as a result of alternative mRNA splicing, with DSPII the shorter isoform of the two. Both are widely expressed in numerous tissues, with DSPII absent from the heart and simple epithelia (Angst et al., 1990). A minor DSP isoform derived from DSPI, named DSPIα, produced by the alternative splicing of DSPI mRNA has also been described, and is detectable in lower levels than those of the dominant isoforms; however, it presents a similar tissue distribution (Cabral et al., 2010b). Using immunogold labelling of DSP, Franke et al. (2006) observed that in normal heart muscle, DSP is located in all plaques of the desmosome-like and fascia-adherens-type junctions, with a very intense signal within the desmosome-like junctions. Several in vivo and in vitro studies support the importance of DSP in desmosome assembly and function, and show its pivotal role in the development of epidermis, neuroepithelium,

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INSIGHTS INTO DESMOSOME BIOLOGY FROM INHERITED HUMAN SKIN DISEASE heart and blood vessels (Gallicano et al., 2001; Vasioukhin et al., 2001). The first reported link of DSP mutations with human skin disease was with autosomal dominant SPPK which presents with a longitudinal pattern of hyperkeratosis (Armstrong et al., 1999). The loss-offunction mutations suggested that the disease mechanism was haploinsufficiency and that the dosage of DSP was critical in stressed areas of the skin such as the palm and sole. Indeed, histology of affected skin revealed loss of suprabasal keratinocyte adhesion. The first reported recessive DSP mutation was identified in Ecuadorian families with Carvajal syndrome: ARVC with dilated cardiomyopathy, woolly hair and SPPK, but also with hyperkeratosis at other stress sites in the skin including the flexures. The homozygous mutation truncates the DSP protein, losing a portion of the IF-binding site leading to loss of cell adhesion and a collapsed IF network (Norgett et al., 2000; Getsios et al., 2004b; Huen et al., 2002). Subsequently, a variety of DSP-associated conditions such as cardiocutaneous syndromes have been reported with varying degrees of severity. As mentioned earlier, heterozygous premature termination codon mutations in exons common to all DSP isoforms (termed haploinsufficiency) underlie dominant non-syndromic SPPK (Armstrong et al., 1999; Whittock et al., 1999). In contrast, the homozygous mutation p.R1267X leads to complete absence of DSPI but to normal levels of DSPII (Uzumcu et al., 2006). This loss of expression of DSPI is associated with autosomal recessive mild epidermolytic PPK (but no obvious keratinocyte adhesion defect), woolly hair and aggressive arrhythmogenic dilated cardiomyopathy, leading to severe ventricular dysfunction and associated arrhythmia at an age in which the cardiac manifestations of desmosomal disease are very rarely encountered. Functional studies in keratinocytes suggest that DSPII plays a more significant role than DSPI in maintaining robust adhesion, supporting cell-type-specific functions for the DSP isoforms (Cabral et al., 2012). Another example of DSP-associated disease includes compound heterozygosity of an amino-terminal missense mutation and a carboxy-terminal nonsense mutation leading to severe keratoderma, skin fragility and woolly hair, or alopecia with or without cardiac involvement (Asimaki et al., 2007; Whittock et al., 2002). Recessive DSP mutations can also underlie severe acantholytic epidermolysis bullosa, a lethal disorder which presents with complete alopecia, neonatal teeth, nail loss and death due to transcutaneous fluid loss as a result of extensive skin erosion (Jonkman et al., 2005). Furthermore, dominant DSP mutations are also linked to non-syndromic ARVC but with no obvious cutaneous phenotype (Rampazzo et al., 2002; Norman, 2005). All these human genetic data suggest that DSP has critical functions in addition to those of cell adhesion and IF stability. It should be

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noted that DSP knockout mice show lethality in early embryonic stages, presumably due to loss of integrity of the embryonic ectoderm (Gallicano et al., 1998). DESMOSOMAL CADHERINS Desmosomal cadherins belong to the larger cadherin superfamily which also includes T-cadherin, FAT family cadherins (Angst et al., 1990), seven-pass transmembrane cadherins, protocadherins and classical cadherins, all sharing an approximately 110 amino acid motif involved in adhesion and calcium binding (Takeichi, 1990). DSGs and DSCs are the transmembrane components that bridge adjacent cells and are embedded in the cytoplasmic plaques, forming the dense extracellular midline seen in mature desmosomes. They share 30% amino acid identity with each other and classical cadherins (Garrod et al., 2002), with DSCs being more closely related to the classical cadherins than to DSGs (Kljuic et al., 2004). Desmosomal cadherins are composed of five extracellular cadherin repeats (EC1-5) containing Ca2⫹binding sites and a cell-adhesion recognition (CAR) site (Tselepis et al., 1998; Runswick et al., 2001). A unique characteristic of all DSCs is the alternative splicing that generates a complete DSCa form and a shortened DSCb form of the protein by the insertion of a mini-exon containing a stop codon, the shortened length of their carboxy-terminal domain being the only difference between the two isoforms (Collins et al., 1991). DSGs contain an extended 500 amino acid tail, the function of which is not fully understood. Desmosomal cadherins show complex developmental and differentiation-specific patterns of expression (Holthofer et al., 2007), which implies that desmosomes within different tissues are biochemically and functionally distinct. The precise role of the tissue-specific expression patterns of desmosomal cadherins has yet to be elucidated, but manipulation of desmosomal cadherin expression suggests that tight regulation of their expression pattern is critical to tissue homeostasis (Bannon et al., 2001). Within the epidermis, these genes are differentially expressed as keratinocytes undergo terminal differentiation (Kottke et al., 2006; Holthofer et al., 2007) as follows: DSG1 and DSC1 are strongly expressed in the granular and spinous layers, their levels decreasing in the lower levels of the epidermis (King et al., 1995; Shimizu et al., 1995; North et al., 1996); DSG2 and DSC2 are expressed in all desmosome-bearing tissues. They represent the predominant isoforms in simple epithelia (Legan et al., 1994; Schafer et al., 1996), and are mainly expressed in the basal layer of stratified epidermis (Garrod et al., 2002; North et al., 1996). DSG4 is primarily expressed in the hair follicle and is restricted to the more differentiated layers in stratified epithelia (Delva et al., 2009). DSGs 1, 3 and 4, and DSCs 1 and 3 are predominantly expressed in the epidermis, while DSG2

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and DSC2 are highly expressed in the myocardium (Li and Radice, 2010). Within the cornified layer of the epidermis (stratum corneum), desmosomes are modified into corneodesmosomes, structures that contain DSG1, DSC1 and corneodesmosin as their major extracellular constituents. Like DSP, the first linkage of desmosomal cadherins with human disease came from the skin with DSG1 haploinsufficiency mutations associated with autosomal dominant SPPK (Figure 1; Kljuic et al., 2003b; Rickman et al., 1999; Awad et al., 2006a). Recently, homozygous loss-of-function DSG1 mutations were identified in an autosomal recessive syndrome characterised by severe dermatitis, allergies and metabolic wasting (SAM) (Samuelov et al., 2013). The mutation carriers in these families presented with non-syndromic SPPK. Mutations in other desmosomal cadherins have also been associated with monogenic human disorders (Table 1). For example, dominant DSC2 and DSG2 mutations have been associated with non-syndromic ARVC (Syrris et al., 2006; Pilichou et al., 2006). A variety of mutations in DSG4 include frameshift, splice-site, missense and nonsense, responsible for the autosomal recessive hair conditions Monilethrix and hypotrichosis (Schaffer et al., 2006; Zlotogorski et al., 2006; Shimomura et al., 2006). In mice, DSG4 deficiency presents with a lanceolate hair phenotype, characterised by sparse, fragile, broken hair shafts, follicular dystrophy and ichthyosiform dermatitis (Jahoda et al., 2004; Bazzi et al., 2005). In humans, a homozygous nonsense DSC3 mutation was identified in a family with autosomal recessive hypotrichosis including absence of eyebrows and eyelashes plus generalised recurrent fluid–filled skin vesicle formation (Ayub et al., 2009). DSC3-deficiency in mice is lethal in the very early embryonic stages. Despite the lack of disease-causing mutations being identified in DSG3 and DSC1 in humans, a DSG3knockout mouse presented with hair loss and loss of epithelial integrity (Koch et al., 1997), while DSC1-

Figure 1. Striate palmoplantar keratoderma associated with an autosomal dominantly inherited loss of function mutation in DSG1.

deficient mice have skin defects which become more apparent 2 days after birth, and later on develop into localised lesions and epidermal fragility with localised hair loss (Chidgey, 2001). THE ARMADILLO FAMILY PG and the PKPs (Hatzfeld, 2005; Hatzfeld, 2007), all members of the armadillo family, are adaptor proteins with roles in facilitating the adhesion of DSP to intermediate filaments, in regulating clustering of desmosomal components, and in mediating important signal transduction pathways. PG PG is composed of 12 arm repeats that share 65% amino acid identity with β-catenin, the equivalent protein associated with adherens junctions. The central armadillo domain of PG interacts with DSP, which in turn tethers intermediate filaments to the desmosomal plaque. PG can also translocate to adherens junctions and bind E-cadherin in the same manner as β-catenin, but its higher affinity for DSP may explain why PG and not β-catenin locates to desmosomes (Choi et al., 2009). The critical role of PG in desmosome assembly was demonstrated using knockout studies in mice. Impaired cell cohesion was observed, indicative of compromised desmosome function. Most knockout mice were embryonic lethal although in some cases mouse pups were born but presented epidermal fragility, heart defects and died shortly after birth (Acehan et al., 2008; Bierkamp et al., 1996; Ruiz et al., 1996). Human genetic studies in individuals from the Greek island of Naxos affected with an autosomal recessive condition known as ‘Naxos disease’, which includes ARVC alongside woolly hair and mild epidermolytic PPK, identified homozygous truncating mutations in JUP encoding PG as the underlying cause of this syndrome (McKoy et al., 2000; Protonotarios & Tsatsopoulou, 2004; Delmar & McKenna, 2010). Another recent study described a recessive missense mutation in JUP in a patient who presented with PPK and total alopecia with a cardiac phenotype (Erken et al., 2011). Pigors et al. reported a lethal phenotype caused by a homozygous nonsense mutation in JUP leading to severe congenital skin fragility with generalised epidermolysis, massive transcutaneous fluid loss and no apparent cardiac dysfunction. The complete loss of PG in patient skin led to fewer desmosomes and no adhesion structures between keratinocytes (Pigors et al., 2011). To add further complexity to the disease mechanisms associated with PG, Cabral et al. (2010a) identified loss of function JUP mutations with a recessive syndrome of skin fragility, diffuse PPK, and woolly hair but no signs of ARVC. Little or no PG expression was detected in the skin of these patients.

INSIGHTS INTO DESMOSOME BIOLOGY FROM INHERITED HUMAN SKIN DISEASE Again like with DSP, these human genetic findings support both overlapping and distinct roles for PG in the epidermis and heart. Recently, Li et al., created an epidermal conditional Jup-knockout mouse model with a skin phenotype of perturbed cell proliferation, apoptosis and differentiation and also compromised immune defence (Li et al., 2012).

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PKPS PKPs play a role in the clustering of desmosomal proteins during the formation of desmosomes. The N-terminal head domain of PKP1 can associate with DSG1, PG, keratin and actin filaments, and ultimately with DSP through what appears to be a robust association that drives DSP recruitment to cell–cell junctions (Kowalczyk et al., 1999; Hatzfeld et al., 2000; Wahl, 2005; Hofmann et al., 2000). PKP3 interacts with the largest number of desmosomal proteins, including DSP, PG, DSG1–DSG3, DSC3a and DSC3b, and DSC1a and DSC2a (Hatzfeld, 2007). PKP2 plays an important role in transporting DSP to the plasma membrane during desmosome assembly, but does so less efficiently than PKP1 (Green et al., 2010; Chen et al., 2002). The mechanism behind PKP1- and PKP3-mediated desmosomal assembly is not yet fully determined, although it appears that PKP2 functions as a scaffold for protein kinase C alpha (PKCα) and regulates DSP association with intermediate filaments (Green et al., 2010; Godsel et al., 2005; Bass-Zubek et al., 2008). Both PKP1 and 2 exist in two isoforms, a shorter ‘a’ form and a longer ‘b’ form (Mertens et al., 1996; Schmidt et al., 1997). The short ‘a’ form is predominant, while the ‘b’ form is found exclusively in the nucleus. The presence of PKP2 in the nucleus is regulated by the 14-3-3 protein and contributes to the RNA polymerase III holoenzyme complex (Desai et al., 2009). PKPs show tissue- and differentiation-specific patterns of expression similar to those of the desmosomal cadherins. It has been observed that while PKP3 shows expression throughout simple epithelia and all layers of stratified epithelia apart from hepatocytes, PKP1 is mostly expressed in the suprabasal layers of stratified epithelia. PKP2 expression extends to simple epithelia, lower layers of stratified epithelia and non-epithelial tissues such as lymph nodes and cardiac muscle, where it is the only isoform present (Heid et al., 1994; Mertens et al., 1996, 1999; Schmidt et al., 1997; Franke et al., 2007; Bonne et al., 1999). A variety of PKP1 mutations including missense, splice-site and nonsense are linked with phenotypes ranging from skin fragility to severe autosomal recessive ectodermal dysplasia, including perioral cracking and inflammation, scant hair, reduced sweating and astigmatism (Boyce et al., 2012; McGrath et al., 1997; Pieperhoff et al., 2010; Tanaka et al., 2009; Zheng et al., 2005; Ersoy-Evans et al., 2006). PKP2 mutations are a major

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genetic cause of non-syndromic autosomal dominant ARVC (Gerull et al., 2004). Pkp2-null mice display mid-gestational embryonic lethality caused by cardiac patterning defects and fragility of the myocardium (Grossmann et al., 2004), alongside retraction of intermediate filaments from the plasma membrane, demonstrating the importance of PKPs in DSP recruitment and intermediate filament tethering to desmosomes (Delva et al., 2009). While no disease-causing mutations have been reported in humans for PKP3, ablation of this isoform in mice results in defective hair follicle morphogenesis, increased keratinocyte proliferation and DSP mislocalisation, leading to susceptibility to dermatitis and secondary alopecia (Sklyarova et al., 2008). MODULATION OF DESMOSOMAL ARCHITECTURE AND ADHESION Desmosomes are not just static structures that keep cells together; instead, they are very dynamic and adaptable complexes as shown by their ability to adopt different conformations with different adhesive affinities, suppressing pathways important for establishing cell polarity and determining the balance between proliferation and differentiation, all through interactions with signalling cascades. The hyper-adhesiveness of desmosomes is regulated by the presence or absence of Ca2⫹, but there are other factors that mediate desmosome assembly and intercellular adhesion. Some of these factors are PKC, proteolytic processing through proteins such as ADAMs and cathepsins/cystatins, EGFR signalling, raft regulation and the yet unclear mechanism of the ubiquitin-proteasome system (UPS; Nekrasova & Green, 2013; Yin et al., 2005; Stahley et al., 2014; Loffek et al., 2012). DSGs and DSCs are the proteins that play key roles in Ca2⫹ regulation, required for strong cell–cell adhesion (Getsios et al., 2004a), by their interaction across the intercellular space, in both a homophilic and a heterophilic manner. Via several binding motifs within their structure, DSGs and DSCs bind Ca2⫹, and assume a rigidified functional conformation (Pokutta & Weis, 2007), increasing the level of adhesion between neighbouring cells and creating what is described as the dense midline of desmosomes. In low-Ca2⫹ conditions, the desmosomal plaque components and membrane proteins are transported to the plasma membrane, together or in separate compartments, but when desmosomal assembly is triggered, cadherins and DSP complexes do not associate as in normal Ca2⫹ conditions and remain separate (Cirillo et al., 2010). During the early stages of desmosome formation, the assembly can reverse between the young and mature phases but ultimately desmosomes mature and can no longer be dissociated by Ca2⫹ depletion (Watt et al., 1984). This is referred to as hyper-adhesion, the result of high-affinity

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and stable adhesive binding of desmosomal components into mature structures; it has not been observed in adherens or tight junctions (Kimura et al., 2007).

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DARIER’S DISEASE Patients with the autosomal-dominant condition Darier’s disease present papules and plaques in seborrhoeic areas, acantholysis, blistering, mucosal lesions and abnormal keratinisation, aggravated by heat, friction, infections and UVB irradiation (Beck et al., 1977; Sakuntabhai et al., 1999). Impaired adhesion, a feature of the disease, is likely to result from changes in DSP trafficking (Celli et al., 2012; Dhitavat et al., 2003; Hobbs et al., 2011). The desmosomal proteins DSP, DSG3 and DSC3 appeared disorganised with a thicker and punctuated distribution under the plasma membrane, while DSG3 and DSC3 also presented perinuclear staining, suggesting that they had been retained in the endoplasmic reticulum (ER). Genetic analysis of patients with Darier’s disease found that mutations in the ATP2A2 gene coding for the SERCA2A Ca2⫹ pump are responsible for this condition (Sakuntabhai et al., 1999). In vitro studies using Darier keratinocytes showed a decreased ER Ca2⫹ concentration (Dode et al., 2003; Foggia et al., 2006; Miyauchi et al., 2006; Pani et al., 2006). Upon Ca2⫹ depletion, misfolded proteins accumulated in the ER leading to induction of the unfolded protein response (UPR; Yoshida, 2007). In Darier’s disease, keratinocytes show constant activation of the UPR-signallingd pathway (Savignac et al., 2014), enhanced further by treatment with Thapsigargin, a specific inhibitor of SERCA pumps (Thastrup et al., 1989). Treatment with Miglustat, an inhibitor of α-glucosidase, reversed the phenotype observed in Darier keratinocytes and allowed normal formation of adherens junctions and desmosomes (Savignac et al., 2014).

ADAM17 ADAM17 (a disintegrin and metalloprotease 17) is responsible for shedding a number of ligands by cleavage of substrates in the juxtamembrane region. Substrates include a number of ligands for the EGF receptor (EGFR) and TNF-α, giving ADAM17 its alternative name TNF-α-converting enzyme. ADAM17 has additionally been shown to play a key role in ligandindependent Notch signalling, and in the shedding of cell adhesion molecules including DSG2 (Gschwind et al., 2003; Klessner et al., 2009; Pruessmeyer & Ludwig, 2009; Sahin et al., 2004; Bech-Serra et al., 2006). Homozygous loss-of-function ADAM17 mutations are associated with a syndrome of severe skin inflammation, increased susceptibility to infection, bowel inflammation and cardiomyopathy (Blaydon et al., 2011a). Adam17 knockout in mice is lethal (Peschon

et al., 1998). Immunohistochemistry with an antibody against DSG1 and DSG2 showed increased staining intensity (Blaydon et al., 2011a) implying a reduction in DSG2 shedding by ADAM17. Thus, the cardiomyopathy and other phenotypes in this syndrome may be related, in part, to impaired ADAM17-mediated DSG2 processing (Blaydon et al., 2011a). In contrast, tylosis with oesophageal cancer (TOC) results in increased processing and activity of ADAM17 (Brooke et al., 2014). TOC patients suffer from PPK, follicular papules, oral keratosis, and up to a 95% lifetime risk of developing oesophageal cancer (Ellis et al., 1994; Hennies et al., 1995; Stevens et al., 1996). TOC results from mutations in a specific region of the long N-terminus of the inactive rhomboid protein iRHOM2, encoded by the gene RHBDF2 (Blaydon et al., 2012; Saarinen et al., 2012). iRHOM2 (and its homologue iRHOM1) traffic ADAM17 from the ER to the Golgi, where the inhibitory pro-domain is cleaved by furin (Adrain et al., 2012; McIlwain et al., 2012). A dramatic increase in the iRHOM2-mediated processing of ADAM17 in TOC cutaneous keratinocytes compared to that of control cells was observed (Brooke et al., 2014). Strikingly, electron microscopy of the skin of TOC patients (Figure 2B) revealed desmosomes lacking the electron-dense midlines seen in non-TOC skin (Brooke et al., 2014), consistent with desmosomes in a woundhealing state (Garrod, 2005). Furthermore, there appeared to be increased processing of DSG2 in TOC cutaneous keratinocytes (Brooke et al., 2014). DSG2 is reported to be expressed at lower levels in epidermis so other cadherins may also be affected. Alternatively, desmosomal remodelling may result from the increased EGFR signalling in TOC keratinocytes shown by increased migration, insensitivity to exogenous EGF (Blaydon et al., 2012) and increased shedding of EGFR ligands (Brooke et al., 2014). EGFR signalling results in phosphorylation of desmosomal cadherins followed by cleavage and endocytosis (Klessner et al., 2009; Lorch et al., 2004), and EGFR inhibition increases adhesion between cells (Lorch et al., 2004), so it is plausible that alterations in desmosomal composition may result from this altered EGFR signalling (Figure 2A). FINAL DISCUSSION A striking aspect of the desmosomal disorders is the wide spectrum of inherited conditions that can arise from a variety of dominant or recessive mutations in genes encoding the desmosomal proteins DSP and PG, in contrast to the more limited phenotypes resulting from mutations in the PKPs and the cadherin superfamily. Despite the increasing number of desmosomal mutations being identified in patients with phenotypes ranging from PPK to acantholysis, hair disruption and/or sudden cardiac death, still the mechanism of protein trafficking to the plasma membrane, desmosome assembly, regulation and signalling is less known. Further-

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Figure 2. ADAM17 and EGFR-mediated regulation of desmosomes. (A) Schematic showing the possible mechanisms of desmosomal regulation by the metalloproteinase enzyme ADAM17. Desmosomes may be disrupted indirectly through ADAM17-mediated shedding of EGFR ligands, leading to desmosomal remodelling through EGFR signalling; or regulated directly via ADAM17-mediated cleavage of DSG2 by ADAM17. Loss-of-function ADAM17 mutations lead to accumulation of cell-surface desmosomal proteins, while increased processing of ADAM17 by iRHOM2 in tylosis with oesophageal cancer causes increased shedding of EGFR ligands and DSG2. (B) In electron microscopy images, a clear electron-dense midline is seen in the desmosomes of normal skin (i) indicating desmosomes in a hyperadhesive state, while desmosomes in TOC skin lack this midline (ii) suggesting that the desmosomes are in a calcium-dependent wound-healing state. EM was carried out by Prof Akemi Ishida-Yamamoto and Graham McPhail.

more, in autosomal dominant disorders such as Darier’s and Hailey Hailey’s disease (Hu et al., 2000), mutations affecting desmosomal regulation do not affect desmosomal proteins directly, but do so through mutations in the Ca2⫹ transport ATPases ATP2A2 and ATP2C1, therefore affecting the essential state of hyper-adhesiveness. More recently, our attention has turned towards protease inhibitors and their target proteases, not towards their protection against allergens in the upper layers of the epidermis, but their direct role in desmosomal homeostasis. In exfoliative ichthyosis, loss-of-function mutations in the protease inhibitor cystatin A (CSTA) destabilise the basal-suprabasal connection in the epidermis (Blaydon et al., 2011b), emphasising a possible role in desmosome regulation through its target proteases. Furthermore, homozygous loss-of-function mutations of ADAM17 lead to a reduction in shedding of DSG2 (Blaydon et al., 2011a), while in TOC patients harbouring iRHOM2 mutations, there is an increased processing and activity of ADAM17, with enhanced DSG2 and also EGFR ligand shedding (Figure 2, Brooke et al., 2014). In summary, the human disorders of the desmosome suggest focussing our attention towards the complexity of regulatory signalling pathways in which desmosomal proteins play orchestrating roles.

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