Desmosomes at a glance

生物 计算生物学 进化生物学 认知科学 心理学
作者
Bhushan V. Desai,Robert M. Harmon,Kathleen J. Green
出处
期刊:Journal of Cell Science [The Company of Biologists]
卷期号:122 (24): 4401-4407 被引量:93
标识
DOI:10.1242/jcs.037457
摘要

Desmosomes are one of four intercellular junctions present on the lateral side of neighboring polarized epithelial cells. Tight junctions and adherens junctions (AJs) are restricted to the apical domain, where they form the epithelial barrier and organize cortical actin, respectively. Desmosomes are found subjacent to the AJs and are more widely distributed along the lateral membranes. By tethering the intermediate filament (IF) cytoskeleton to the plasma membrane, these strongly adhesive junctions further enhance their force-resisting mechanical properties (see Poster, panels 1 and 3). Interspersed among desmosomes are `communicating' or gap junctions that chemically and electrically couple cells. Desmosomes confer stability to tissues that experience mechanical stress such as the epidermis and heart, and are also found in more specialized junctions of the meninges and lymphatic endothelial cells (reviewed by Getsios et al., 2004; Green and Simpson, 2007; Holthofer et al., 2007).It has recently emerged that desmosomal cadherins and their associated proteins play a role in instructing the development and differentiation of complex tissues in vertebrates. In addition, they are frequently mutated in inherited diseases of the skin and heart and are targeted by autoimmune antibodies and bacterial toxins, the latter of which can result in blistering of complex epithelia (McGrath, 2005; Waschke, 2008). This Cell Science at a Glance article and its accompanying poster highlight key aspects of desmosome structure, function and regulation, and relate this knowledge to recent advances in our understanding of the role of desmosomes in human disease. Interested readers are referred to more comprehensive recent reviews for further details (Bazzi and Christiano, 2007; Dusek et al., 2007; Garrod and Chidgey, 2008; Getsios et al., 2004; Green and Simpson, 2007; Holthofer et al., 2007; Huber, 2003; McGrath, 2005; Schmidt and Koch, 2007; Waschke, 2008).At the ultrastructural level, desmosomes appear as multi-layered, bilaterally symmetrical structures featuring a pair of electron-dense plaques that sandwich an extracellular region of ∼35 nm in width. This extracellular space is bisected by a central dense line (dense midline) comprising the desmosomal cadherin ectodomains (see Poster, panel 3). The major components of desmosomes come from three protein families: cadherins, armadillo proteins and plakins (see Poster, panels 2 and 3). On the extracellular face of the plasma membrane, the desmosomal cadherins engage in calcium (Ca2+)-dependent adhesive interactions, whereas on the cytoplasmic side, they are indirectly linked to the IF cytoskeleton via their interactions with armadillo and plakin family members (see Poster, panel 3). Although a minimal set of these core proteins is required for desmosome formation, additional components tailor desmosomes for specialized functions in a cell-type-specific manner. These additional components include proteins that are required for junction assembly and integrity [such as the p63 effector PERP, pinin and the prion protein PrP(c)], proteins that contribute to the cornified envelope and corneodesmosomes (such as envoplakin, periplakin and corneodesmosin), and proteins involved in cytoskeletal remodeling, differentiation and signaling (such as the periplakin-binding protein kazrin and the ErbB2-binding protein Erbin) (Green and Simpson, 2007; Huber, 2003; Sonnenberg and Liem, 2007).Desmosomal cadherins are the desmosome counterparts of the classic cadherins that are present in AJs. They are subdivided into desmogleins 1-4 (Dsg1-Dsg4) and desmocollins 1-3 (Dsc1-Dsc3); the genes encoding these proteins are organized in a tandem array along mouse and human chromosome 18. Whereas Dsg2 and Dsc2 are commonly found in desmosome-containing tissues, Dsg1 and Dsc1 (as well as Dsg3 and Dsc3) are restricted to stratified epithelia, where they are organized in reciprocal overlapping patterns in the upper and lower layers, respectively (see Poster, panel 4). Dsg4 is also expressed in differentiated layers of the epidermis and associated hair follicles. Desmocollins exist as two splice variants: the more typical type `a' form and the shorter type `b' form, which lacks plakoglobin (Pg)-binding ability and is capped with 11 residues in Dsc1 and Dsc2, and eight residues in Dsc3 that are not found in the Dsc type `a' isoform (see Poster, panel 2).Dsgs and Dscs are similar to classic cadherins in that they contain a series of highly conserved extracellular repeat (EC) domains, followed by a short transmembrane domain (TM). Whereas classic cadherins interact in a homophilic manner via the exchange of highly conserved tryptophans on adjacent cadherin EC1 ectodomains into the hydrophobic pockets of their partner, the nature of the interactions that occur between desmosomal cadherins, and their preferred partnerships in vivo, are not well understood. Although high-resolution tomographic studies of desmosomes in situ revealed a somewhat disordered array of desmosomal cadherin ectodomains, more recent cryoelectron microscopy studies suggest a highly ordered arrangement of cadherins. These findings could help explain the robust adhesive properties of desmosomes in vivo. Similar to classic cadherins, the EC1 domain of desmosomal cadherins is crucial for adhesion and might participate in both heterophilic and homophilic interactions. The cytoplasmic domains contain an intracellular anchor (IA), a catenin-binding region (ICS) and, in desmogleins, additional unique domains that include the intracellular proline-rich linker (IPL), variable numbers of repeated unit domains (RUDs) and a desmoglein terminal domain (DTD) (Garrod and Chidgey, 2008; Getsios et al., 2004; Holthofer et al., 2007). Established binding partners for desmosomal cadherins are Pg and plakophilins (Pkps), but the extended, highly divergent desmosomal cadherin tails might provide a docking site for additional structural and signaling proteins (Table 1).Desmosomal armadillo family members include Pg and Pkps 1-3. Similar to their AJ counterparts β-catenin and p120 catenin, Pg and Pkps are also present in the nucleus. Pkp1 and Pkp2 each have two isoforms, the shorter `a' form and the longer `b' form, the Pkp1b form being exclusively nuclear. The presence of Pkp2 in the nucleus, where it contributes to the RNA polymerase III holoenzyme complex, is regulated by the 14-3-3 protein. It has been reported that a fourth Pkp-like molecule, known as p0071 (Pkp4), associates with desmosomes and AJs, although recently its desmosomal location has been questioned (Hofmann et al., 2009). Pg comprises 12 central arm repeats, which are flanked by N- and C-terminal domains. By interacting with both the ICS domain of the desmosomal cadherins and the N-terminus of the IF-anchoring protein desmoplakin (DP), Pg is positioned to play a role in linking IFs to the plaque. In addition to its junctional roles, Pg regulates cell growth, survival and differentiation indirectly through its influence on β-catenin signaling, and directly through transcriptional pathways that have yet to be fully elucidated (Hatzfeld, 2007; Holthofer et al., 2007; Keil et al., 2007).Pkp1 is found only in desmosomes of complex epithelia, whereas Pkp2 and Pkp3 are more widely distributed and are also more promiscuous in their protein partnerships than Pg. So far, no binding partners for the nine armadillo repeats of the Pkps have been identified, although it is known that their extended N-terminal head domains can associate with DP, multiple desmosomal cadherins, Pg, β-catenin and/or cytokeratins, depending on the Pkp isoform (see Table 1). These numerous partnerships expand the number of lateral interactions that can occur in the plaque. Pkps have been proposed as scaffolds for positioning the regulatory molecules protein kinase C (PKC) and Rho GTPases in locations where they are needed to promote junction assembly and other functions. In response to cellular stress, both Pkp3 and Pkp1 are recruited to granules that are known to accumulate stalled translation initiation complexes, which suggests that Pkps might also have a role in RNA metabolism (Bass-Zubek et al., 2008; Hatzfeld, 2007).Plakins are a family of large, modular proteins that link various cytoskeletal elements with each other and with plasma membranes. Of four plakin family members that have been reported to associate with desmosomes (DP, plectin, envoplakin and periplakin), DP is indispensable for desmosome assembly and IF anchorage; DP-deficient mouse embryos do not survive beyond E6.5. DP, which is expressed as two alternatively spliced isoforms (DPI and DPII), is a long dumbbell-shaped molecule that is divided into three domains (see Poster, panel 2): the N-terminal head domain binds to armadillo proteins and to Dsc1a, and targets DP to the desmosomal plaque; the central rod domain is required for DP oligomerization; and the C-terminal domain (comprising three plakin repeats – A, B and C) links the desmosomal complex to the IF cytoskeleton (Garrod and Chidgey, 2008; Holthofer et al., 2007; Sonnenberg and Liem, 2007). The phosphorylation status of the extreme C-terminal region regulates the interaction between DP and IFs (Stappenbeck et al., 1994). In addition to its absolute requirement for maintaining tissue integrity, DP has also been implicated in regulating cellular proliferation by affecting the ERK-Akt signaling pathway (Wan et al., 2007) and in governing the redistribution of microtubules during epidermal differentiation (Lechler and Fuchs, 2007).The dynamic nature of desmosomes is illustrated by live-cell imaging observations in cultured cells, revealing their constant remodeling and the exchange of GFP-labeled desmosome molecules into existing plaques. De novo assembly of cell-cell junctions in contact-naïve cells, or in response to an increase in extracellular Ca2+, occurs from distinct cytoplasmic pools of cadherin core and plaque components. Desmosomal cadherins are constitutively synthesized and transported to the membrane, probably in part via long-range microtubule-dependent processes. In response to cell-cell contact, desmosomal cadherins become stabilized and cluster at the cell surface in conjunction with plaque proteins. In addition, DP-enriched precursor particles form in the cytoplasm in response to cell-cell contact. These particles then translocate to nascent desmosomes to reinforce the plaque in an actin-dependent manner about 30 minutes following contact. A proportion of the cellular pool of Pkp2 associates with these DP precursors and plays an essential role in regulating both the association of DP with IFs and its dynamic behavior. Pkp2 might accomplish this by serving as a scaffold to recruit active PKCα to DP, resulting in DP phosphorylation and conversion to an assembly-competent state. Pkp1 recruits itself to cell-cell interfaces through its C-terminal domain, and DP through its N-terminal domain (Holthofer et al., 2007). By recruiting plaque proteins such as DP, armadillo family members enhance the structural integrity of cell-cell junctions and have a positive effect on the size and number of desmosomes.Desmosomes and AJs exhibit a symbiotic relationship: desmosome formation depends on the presence of AJs, whereas the maturation of AJs and the associated cortical actin cytoskeleton depends on functional desmosomes. A variety of structural and signaling mediators are important for this relationship. Armadillo proteins might `seed' the de novo formation of desmosomes through their ability to associate with both classic and desmosomal cadherins and subsequently dictate their segregation into distinct junctions in epithelial tissues. Desmosomal-plaque assembly is actin-dependent and might require actin remodeling, which can be triggered by the ligation of classic cadherins. These events are associated with the maturation of AJs and are coordinated with biochemical signaling pathways. For instance, PKC activation can circumvent the requirement for AJs in directing the formation of desmosomes, suggesting a potential role for this protein kinase in mediating crosstalk. Nectin-1, a member of a subfamily of immunoglobulin-like adhesion molecules known to regulate AJs and tight junctions, is also emerging as a potential regulator of desmosome assembly (Barron et al., 2008; Hatsell and Cowin, 2001; Hatzfeld, 2007). Collectively, these observations underscore the interdependency of intercellular junctions from their de novo assembly to their function during tissue homeostasis.The stability of desmosomes in subconfluent or freshly plated cultured cells depends on extracellular Ca2+. Acute Ca2+ depletion causes the engulfment of desmosomal plaques and associated IFs, whereas protein kinase inhibition prevents loss of adhesion and accompanying internalization (Garrod and Kimura, 2008). In addition, cholinergic receptors, receptor tyrosine kinases, proteolytic processing by ADAM (a disintegrin and metalloproteinase) sheddases and pathogenic pemphigus autoantibodies have all been implicated in junctional destabilization through their capacity to promote desmosomal cadherin internalization and/or to weaken interactions between desmosomal cadherins and IFs (Delva and Kowalczyk, 2009; Grando, 2006; Kottke et al., 2006; Muller et al., 2008; Waschke, 2008). Although PKCα promotes desmosome assembly, its activity is attenuated during junctional maturation, leading to the formation of hyperadhesive Ca2+-independent desmosomes. In fact, in tissues, most desmosomes exhibit this hyperadhesive state. However, both epithelial sheets in vitro and desmosomes in vivo can convert to a Ca2+-dependent state after wounding, possibly in response to re-activation of PKCα, which becomes closely associated with the plaque region during this conversion process (Garrod and Kimura, 2008). Although molecular targets of PKC that contribute to this conversion have not been identified, one candidate could be DP, whose solubility and assembly state are regulated by serine phosphorylation (Holthofer et al., 2007). RhoA, of the Rho family of small GTPases, is also implicated in regulating desmosome-mediated adhesion in patients with pemphigus, who suffer from epidermal blistering caused by circulating autoimmune anti-Dsg antibodies. Antibody-mediated loss of intercellular adhesion is inhibited by specific activation of RhoA, and inactivation of RhoA results in pemphigus-like epidermal splitting (Waschke, 2008). Thus, desmosomes are subject to cues from both the normal tissue environment and pathogenic processes that regulate their assembly state and adhesive strength.Desmosomes are crucial for normal morphogenesis during all stages of embryogenesis. Investigation of knockout mice has shown that the lack of several desmosomal components (DP, Dsg2, Dsc3 or Pg) results in early embryonic lethality. In addition, Dsg2 deficiency leads to defects in embryonic stem-cell viability and proliferation, even prior to the appearance of desmosomes, which reveals an adhesion-independent role for this cadherin. Pg- or Pkp2-null mice have lethal defects in embryonic heart development. Hyperproliferative and differentiation disorders have also been reported following expression of dominant-negative desmosomal cadherins or the targeted mis-expression of desmosomal cadherins in the suprabasal layers of the epidermis. These studies reveal the importance of desmosomes as structural mediators of tissue integrity, and demonstrate that they can influence proliferative signaling pathways (Bazzi and Christiano, 2007; Cheng and Koch, 2004; Garrod and Chidgey, 2008; Huber, 2003; Muller et al., 2008; Schmidt and Koch, 2007).Human diseases show similarities to the deficiencies that have been observed in engineered animal models. Mis-sense, truncation and/or nonsense mutations leading to haplo-insufficiency have been identified in representatives of all major desmosome families, including DP, Pkps, Pg, the desmosomal caherins and also corneodesmosin (Table 2 and Poster, panel 5). These mutations can lead to skin diseases with symptoms ranging from mild keratodermas to severe lethal acantholysis. An overlapping subset of mutations leads to arrhythmogenic right ventricular cardiomyopathy (ARVC) (McGrath, 2005; Schmidt and Koch, 2007). The pathology of ARVC involves fibrofatty replacement of cardiomyocytes, ventricular arrhythmias, heart failure and sudden death. These outcomes might result from various defects, including abnormal gap-junction function and β-catenin-dependent signaling. For example, Pkp2-deficiency, which accounts for the majority of reported ARVC cases, results in a loss of plasma-membrane-associated Cx43 and thus might affect electrical coupling of cardiac myocytes (Bass-Zubek et al., 2009). Alterations in β-catenin-dependent signaling in a DP mouse model of ARVC were reported to contribute to a transcriptionally driven conversion to an adipocyte cell fate, possibly owing to aberrant redistribution of DP-associated Pg into the nucleus. Finally, mutations in sarcoplasmic/endoplasmic-reticulum Ca2+ pump gene 2 (SERCA2) impair desmosome assembly and lead to loss of cell-cell adhesion in epidermal keratinocytes of Darier's disease patients, consistent with the importance of intracellular Ca2+ homeostasis in desmosome function.Desmosomal cadherins are also targets of autoimmune antibodies in pemphigus vulgaris (PV) and pemphigus foliaceus (PF) (Table 2). Antibodies directed against the extracellular domains of Dsg1 and Dsg3 lead to epidermal blistering through molecular mechanisms that can involve steric hindrance, endocytic internalization, impaired desmosome assembly and/or the triggering of signaling pathways that cause cell-cell dissociation. Bacterial toxins produced by Staphylococcus aureus, which causes the proteolytic removal of the Dsg1 extracellular domain, also result in superficial skin blistering that appears identical to that observed in PF (Payne et al., 2004; Stanley and Amagai, 2006). Both antibody- and toxin-mediated pathogenesis have been replicated in a mouse model using pathogenic and non-pathogenic PF anti-Dsg1 antibodies and exfoliative toxin A, respectively. This blistering phenotype contrasts dramatically with the thickened hyperkeratotic state of the epidermis from human patients with genetic alterations in the same Dsg1 molecule, for reasons that are not fully understood (see Table 2).Desmosomal cadherins and their associated proteins have been linked with cell proliferation and survival pathways, and might contribute to regulation of tumor-cell growth, invasion and metastasis. Dsgs and their binding partner Pg can sensitize cells to apoptotic stimuli, and Dsg internalization is enhanced by epidermal growth factor receptor (EGFR)- and ADAM-family-dependent Dsg2 ectodomain shedding, which might promote tumor-cell migration. In certain contexts, the overexpression of Pg has been associated with increased chromosomal instability and uncontrolled proliferation via increased protein expression of pituitary-tumor-transforming gene and Myc, whereas in epidermal keratinocytes, it has been demonstrated that Pg is required for suppression of the transcriptional activation of Myc. Finally, the transcription of desmosomal genes is attenuated by factors such as zinc finger E-box binding homeobox 1 (ZEB1) and ZEB2, which regulate epithelial-to-mesenchymal transition and promote tumor invasion and metastasis (Chidgey and Dawson, 2007; Garrod, 1995; Klessner et al., 2008; Muller et al., 2008; Pan et al., 2007).Like AJs, desmosomes are dual regulators of cell adhesion and morphogenesis. Whereas AJs play an active role in tissue remodeling, which involves rearrangements of the actin cytoskeleton, the fact that desmosomes interact with IFs puts them at center stage in the maintenance of tissue integrity. Desmosomes also guide differentiation and morphogenesis in complex tissues. However, we still know surprisingly little about how differentiation-dependent patterns of desmosomal cadherins are controlled via transcriptional regulation, or how these patterns dictate cadherin organization in situ. Studies that aim to define desmosomal cadherin structure and the nature of the proteins that interact with their unique cytoplasmic tails are needed to better understand how they are organized and how they perform their structural and signaling roles. Recent advances in genetic and proteomic screening will facilitate future progress in these areas, whereas advances in optical imaging promise to provide insights into the assembly pathways that govern the dynamics of these insoluble organelles. Finally, coupling these state-of-the-art strategies with electrophysiological approaches will further our understanding of the mechanisms that lead to cardiac disease caused by desmosome defects.
最长约 10秒,即可获得该文献文件

科研通智能强力驱动
Strongly Powered by AbleSci AI
更新
大幅提高文件上传限制,最高150M (2024-4-1)

科研通是完全免费的文献互助平台,具备全网最快的应助速度,最高的求助完成率。 对每一个文献求助,科研通都将尽心尽力,给求助人一个满意的交代。
实时播报
Jasper应助小何采纳,获得10
刚刚
ifonly发布了新的文献求助10
刚刚
酷酷从雪发布了新的文献求助10
1秒前
1秒前
天天快乐应助tt采纳,获得30
2秒前
2秒前
tamaco发布了新的文献求助10
2秒前
Sudon完成签到 ,获得积分10
2秒前
欢呼山雁发布了新的文献求助10
2秒前
瞬间完成签到,获得积分10
3秒前
try发布了新的文献求助10
3秒前
科研通AI2S应助熊玉然采纳,获得10
3秒前
4秒前
大雪发布了新的文献求助10
4秒前
4秒前
华仔应助滕侑林采纳,获得10
4秒前
Akim应助orange9采纳,获得10
5秒前
瞬间发布了新的文献求助10
6秒前
浅尝离白应助年轻芷烟采纳,获得30
6秒前
lynn完成签到,获得积分20
7秒前
云淡风清完成签到,获得积分10
7秒前
8秒前
Ava应助hxl采纳,获得10
8秒前
jituher发布了新的文献求助30
8秒前
8秒前
8秒前
9秒前
10秒前
汉堡包应助zhangxr采纳,获得10
10秒前
jz发布了新的文献求助10
10秒前
科研通AI2S应助wxl采纳,获得10
10秒前
11秒前
李爱国应助King采纳,获得10
11秒前
科研小白完成签到,获得积分10
11秒前
11秒前
华仔应助jituher采纳,获得30
11秒前
12秒前
orange9完成签到,获得积分10
12秒前
ZXT完成签到 ,获得积分10
12秒前
14秒前
高分求助中
Sustainability in Tides Chemistry 2800
The Young builders of New china : the visit of the delegation of the WFDY to the Chinese People's Republic 1000
юрские динозавры восточного забайкалья 800
Foreign Policy of the French Second Empire: A Bibliography 500
Chen Hansheng: China’s Last Romantic Revolutionary 500
XAFS for Everyone 500
Classics in Total Synthesis IV 400
热门求助领域 (近24小时)
化学 医学 生物 材料科学 工程类 有机化学 生物化学 物理 内科学 纳米技术 计算机科学 化学工程 复合材料 基因 遗传学 催化作用 物理化学 免疫学 量子力学 细胞生物学
热门帖子
关注 科研通微信公众号,转发送积分 3144274
求助须知:如何正确求助?哪些是违规求助? 2795879
关于积分的说明 7816861
捐赠科研通 2451946
什么是DOI,文献DOI怎么找? 1304774
科研通“疑难数据库(出版商)”最低求助积分说明 627291
版权声明 601419