Corneodesmosin, a Component of Epidermal Corneocyte Desmosomes, Displays Homophilic Adhesive Properties

Jonca, Nathalie; Guerrin, Marina; Hadjiolova, Krassimira V.; Caubet, Cécile; Gallinaro, Hélène; Simon, Michel; Serre, Guy

doi:10.1074/jbc.m108438200

Cited by 108 publications

(101 citation statements)

References 18 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…This reinforced the hypothesis that HSS is not caused by Cdsn haploinsufficiency [30,31]. Given our previous finding that a recombinant truncated form of CDSN is able to bind the entire CDSN [13,14], a dominant negative interaction between the mutant and wild-type proteins may account for the loss of cohesion in the inner root sheath of the hair follicles. This could affect the functionality of the inner root sheath, such as a decrease in diffusion barrier function resulting in anagen to catagen transition and perturbation of a hair cycle reinitiation.…”

Section: Cdsn and Human Diseasessupporting

confidence: 48%

“…CDSN thus anchored at the cell surface mediates cellular aggregation. Overlay binding assays and quantitative analysis by surface plasmon resonance using bacterial recombinant forms of full-length CDSN confirmed the homophilic adhesive properties of the protein [13,14]. Moreover, recombinant CDSN associates into large homooligomers of at least three subunits that are only partially dissociated in 8 M urea.…”

Section: Cdsn Is An Adhesive Proteinmentioning

confidence: 82%

“…Finally, the underlying molecular mechanism by which CDSN assumes its adhesive function within the corneodesmosome has not been fully elucidated. The previously demonstrated homophilic adhesive properties of CDSN and the strong resistance of aggregates formed by bacterially recombinant CDSN to highly denaturing conditions [13,14] suggested that, in vivo, CDSN reinforced cohesion by its own adhesive properties. However, adhesion provided by glycine-loop domains has been suggested to mediate reversible and constantly adjustable intermolecular links [8].…”

Section: Conclusion -Future Prospectsmentioning

confidence: 99%

See 2 more Smart Citations

Corneodesmosin: Structure, Function and Involvement in Pathophysiology

Jonca¹,

Caubet²,

Guerrin³

et al. 2010

TODJ

Self Cite

View full text Add to dashboard Cite

Corneodesmosin (CDSN) was identified in the early 90 th by raising monoclonal antibodies against human plantar stratum corneum. It is a protein specific to desmosomes that will undergo transformation into corneodesmosomes, i.e. in man, desmosomes of the epidermis, of the three epithelial layers of the inner root sheath of the hair follicles and of the hard palate epithelium. After its secretion by granular keratinocytes via the lamellar bodies, CDSN is incorporated into the desmoglea of the desmosomes shortly before their transformation into corneodesmosomes. CDSN displays adhesive properties, mostly attributable to its N-terminal glycine-rich domain, and is sequentially proteolyzed as corneocytes migrate towards the skin surface. The recent inactivation of Cdsn in mice induced a lethal epidermal barrier disruption and hair follicle degeneration related to desmosome dysfunction, confirming the essential role of the protein in epidermis and hair follicle integrity. CDSN is located on chromosome 6, in the major psoriasis susceptibility locus PSORS1. Intriguingly, the only monogenic disease identified so far associated with nonsense mutations in CDSN, leading to the formation of a truncated protein, is a rare autosomal dominant disease, hypotrichosis simplex of the scalp. In this review, we expose data from the discovery of the protein to the most recent findings related to the relationship between its structure and function. In particular, the important benefits of mouse models and human diseases for the comprehension of CDSN role in the epidermis and hair follicles are reported in details.

show abstract

Section: Cdsn and Human Diseasessupporting

confidence: 48%

Section: Cdsn Is An Adhesive Proteinmentioning

confidence: 82%

Section: Conclusion -Future Prospectsmentioning

confidence: 99%

See 1 more Smart Citation

Corneodesmosin: Structure, Function and Involvement in Pathophysiology

Jonca¹,

Caubet²,

Guerrin³

et al. 2010

TODJ

Self Cite

View full text Add to dashboard Cite

show abstract

“…CDSN has been hypothesized to stabilize desmosomes and to become covalently associated with the cornified cell envelope (CE) . Furthermore, expression of a chimeric protein consisting of the N-terminal domain of CDSN and the transmembrane domain of E-cadherin promotes cell-cell aggregation in transfection experiments, suggesting that CDSN might function as a homophilic adhesion molecule (Jonca et al 2002). Within normal skin, CDSN is progressively proteolysed during cornification and desquamation (Simon et al , 2001).…”

Section: Resultsmentioning

confidence: 99%

Epidermal detachment, desmosomal dissociation, and destabilization of corneodesmosin in Spink5^-/- mice

Yang

Liang²,

Koch³

et al. 2004

Genes Dev.

103

View full text Add to dashboard Cite

Netherton syndrome (NS) is a human autosomal recessive skin disease caused by mutations in the SPINK5 gene, which encodes the putative proteinase inhibitor LEKTI. We have generated a transgenic mouse line with an insertional mutation that inactivated the mouse SPINK5 ortholog. Mutant mice exhibit fragile stratum corneum and perinatal death due to dehydration. Our analysis suggests that the phenotype is a consequence of desmosomal fragility associated with premature proteolysis of corneodesmosin, an extracellular desmosomal component. Our mouse mutant provides a model system for molecular studies of desmosomal stability and keratinocyte adhesion, and for designing therapeutic strategies to treat NS.Supplemental material is available at http://www.genesdev.org.Received June 17, 2004; revised version accepted August 6, 2004. Netherton Syndrome (NS) (MIM 256500) is a severe, recessively inherited skin disease in humans with high neonatal lethality. It is characterized by ichthyosiform erythroderma, atopic dermatitis, bamboo hair, skin barrier defects, and elevated IgE levels in survivors (Krafchik and Toole 1983;Judge et al. 1994). Mutations have been identified in the SPINK5 (serine proteinase inhibitor Kazal type 5) gene of NS patients (Chavanas et al. 2000;Sprecher et al. 2001;Walley et al. 2001;Bitoun et al. 2002;Komatsu et al. 2002). SPINK5 encodes LEKTI (lympho-epithelial Kazal-type-related inhibitor), which is a putative proteinase inhibitor that contains an N-terminal signal peptide and 15 domains with high internal homology (Magert et al. 1999). Each domain has four conserved cysteines. Domains 2 and 15 possess two additional cysteines, which make them typical Kazal-type proteinase inhibitor domains (Magert et al. 1999). LEKTI exhibits proteinase inhibitor activity in vitro (Magert et al. 1999;Komatsu et al. 2002;Walden et al. 2002;Mitsudo et al. 2003). In NS patients, loss or reduction of LEKTI activity is presumed to result in elevated proteolytic activity in the suprabasal epidermis, leading to erythroderma and skin-barrier defects. However, the specific proteins that are targeted for degradation in these patients have not been identified. We describe here a Spink5 mutant mouse line that shows severe skin defects associated with desmosomal fragility, and thus, provides insights into the molecular pathogenesis of NS and a novel model system for studies of keratinocyte adhesion. Results and DiscussionTransgenic mouse line OVE1498 was generated by coinjection of a tyrosinase-tagged (Yokoyama et al. 1990) Sleeping Beauty transposon (Ivics et al. 1997) (termed pT-Tybs-3ЈE) along with PGK2-SB10 (Ivics et al. 1997) (see Supplementary Fig. S1) into inbred FVB/N embryos. The transgenic founder and its transgenic F1 offspring were phenotypically normal and showed no evidence for transposition of the transgene(s) (data not shown). When transgenic F1 mice were intercrossed, ∼25% of the newborn offspring developed severe skin blistering and water barrier defects, leading to death within several hours after birth ...

show abstract

“…Like other type II keratins found in epidermis, the tail domain of K5 features glycine loop motifs (Steinert et al, 1991), which also occur in other epidermal structural proteins (loricrin and corneodesmosin) and in single-stranded RNA binding proteins (Steinert et al, 1991). There is emerging evidence that glycine loops could mediate homophilic interactions (Jonca et al, 2002;Caubet et al, 2004). Clearly, additional studies are needed to identify the mechanism(s) that underlie the distribution of K5's tail domain in transfected cells.…”

Section: Properties Of Keratin 5 Tail Domain Mutantmentioning

confidence: 99%

Defining the Properties of the Nonhelical Tail Domain in Type II Keratin 5: Insight from a Bullous Disease-causing Mutation

2005

MBoC

View full text Add to dashboard Cite

Inherited mutations in the intermediate filament (IF) proteins keratin 5 (K5) or keratin 14 (K14) cause epidermolysis bullosa simplex (EBS), in which basal layer keratinocytes rupture upon trauma to the epidermis. Most mutations are missense alleles affecting amino acids located in the central ␣-helical rod domain of K5 and K14. Here, we study the properties of an unusual EBS-causing mutation in which a nucleotide deletion (1649delG) alters the last 41 amino acids and adds 35 residues to the C terminus of K5. Relative to wild type, filaments coassembled in vitro from purified K5-1649delG and K14 proteins are shorter and exhibit weak viscoelastic properties when placed under strain. Loss of the C-terminal 41 residues contributes to these alterations. When transfected in cultured epithelial cells, K5-1649delG incorporates into preexisting keratin IFs and also forms multiple small aggregates that often colocalize with hsp70 in the cytoplasm. Aggregation is purely a function of the K5-1649delG tail domain; in contrast, the cloned 109 residue-long tail domain from wild type K5 is distributed throughout the cytoplasm and colocalizes partly with keratin IFs. These data provide a mechanistic basis for the cell fragility seen in individuals bearing the K5-1649delG allele, and point to the role of the C-terminal 41 residues in determining K5's assembly properties. INTRODUCTIONIntermediate filaments (IFs) are encoded by a large family of genes comprising Ͼ67 members in the human and mouse genomes Hesse et al., 2001). These 10-to 12-nm wide filaments are prominent structural constituents of the cytoplasm and nucleus in multicellular eukaryotes, but they are distinct from F-actin and microtubules in several key respects. Among them is their association with disease. Inherited mutations in IF proteins are associated with nearly 30 human diseases (Omary et al., 2004). These conditions are dominantly inherited with rare exceptions (Fuchs and Cleveland, 1998;Cassidy et al., 2002;Omary et al., 2004), consistent with the complexity of the assembly pathway and of the architecture of mature IF polymers (Herrmann and Aebi, 2004). Cell and tissue fragility underlies lesion pathogenesis in many of these disorders, reflecting the major function of structural scaffolding fulfilled by IFs in both the cytoplasm and nucleus (Omary et al., 2004;Worman and Courvalin, 2004). Types I and II keratin genes together represent ϳ75% of IF genes and are specifically expressed in epithelial cells Hesse et al., 2001). In part because of a strict heteropolymerization requirement at the protein level (Herrmann and Aebi, 2004), type I and type II keratin genes are tightly regulated in a pairwise and differentiation-related manner in epithelial tissues (Moll et al., 1982;O'Guin et al., 1990;Fuchs, 1995). Correlating with frequent exposure to mechanical stress, epithelia lining up the skin and oral mucosa are keratin rich and sensitive to mutations compromising the structural scaffolding function of keratin IFs. Accordingly, a large fraction of the known IF...

show abstract

Corneodesmosin, a Component of Epidermal Corneocyte Desmosomes, Displays Homophilic Adhesive Properties

Cited by 108 publications

References 18 publications

Corneodesmosin: Structure, Function and Involvement in Pathophysiology

Corneodesmosin: Structure, Function and Involvement in Pathophysiology

Epidermal detachment, desmosomal dissociation, and destabilization of corneodesmosin in Spink5^-/- mice

Defining the Properties of the Nonhelical Tail Domain in Type II Keratin 5: Insight from a Bullous Disease-causing Mutation

Contact Info

Product

Resources

About

Corneodesmosin, a Component of Epidermal Corneocyte Desmosomes, Displays Homophilic Adhesive Properties

Cited by 108 publications

References 18 publications

Corneodesmosin: Structure, Function and Involvement in Pathophysiology

Corneodesmosin: Structure, Function and Involvement in Pathophysiology

Epidermal detachment, desmosomal dissociation, and destabilization of corneodesmosin in Spink5-/- mice

Defining the Properties of the Nonhelical Tail Domain in Type II Keratin 5: Insight from a Bullous Disease-causing Mutation

Contact Info

Product

Resources

About

Epidermal detachment, desmosomal dissociation, and destabilization of corneodesmosin in Spink5^-/- mice