Corneodesmosomes and corneodesmosin: from the stratum corneum cohesion to the pathophysiology of genodermatoses.

Corneodesmosin (CDSN) was identified 20 years ago by raising monoclonal antibodies against human plantar stratum corneum. The protein is specific to corneodesmosomes, cell-junction structures that, in humans, are found in the epidermis, the hard palate epithelium, and the inner root sheath of the hair follicles. Synthesized by the granular keratinocytes and secreted via the lamellar bodies, CDSN is incorporated into the desmoglea of the desmosomes, shortly before their transformation into corneodesmosomes during cornification.

The ubiquitous dermokine delta activates Rab5 function in the early endocytic pathway.

The expression of the recently identified dermokine (Dmkn) gene leads to four families of proteins with as yet unknown functions. The secreted α, β and γ isoforms share an epidermis-restricted expression pattern, whereas the δ isoform is intracellular and ubiquitous. To get an insight into Dmknδ function, we performed yeast two-hybrid screening and identified the small GTPases Rab5 as partners for Dmknδ.

A large-scale multi-technique approach identifies forty-nine new players of keratinocyte terminal differentiation in human epidermis.

At the latest stage of terminal differentiation in the epidermis, granular keratinocytes (GKs) undergo cornification, a programmed cell death required for the establishment of a functional skin barrier. A complex genetic regulatory network orchestrates the underlying biochemical modifications, but very few transcription factors specific to this programme have been identified to date. Here, we describe a large-scale, multi-technique approach performed on cells purified from normal human epidermis, primarily focusing on the identification of regulators.

Corneodesmosin gene ablation induces lethal skin-barrier disruption and hair-follicle degeneration related to desmosome dysfunction.

Corneodesmosin (CDSN) is specific to desmosomes of epithelia undergoing cornification, mainly the epidermis and the inner root sheath of the hair follicles. CDSN nonsense mutations are associated with hypotrichosis simplex of the scalp, a rare disease that leads to complete baldness in young adults. CDSN displays adhesive properties, mostly attributable to its N-terminal glycine-rich domain, and is sequentially proteolyzed as corneocytes migrate towards the skin surface.

Binding of alpha2ML1 to the low density lipoprotein receptor-related protein 1 (LRP1) reveals a new role for LRP1 in the human epidermis.

Background: The multifunctional receptor LRP1 has been shown to bind and internalize a large number of protein ligands with biological importance such as the pan-protease inhibitor alpha2-macroglobulin (alpha2M). We recently identified Alpha2ML1, a new member of the alpha2M gene family, expressed in epidermis. alpha2ML1 might contribute to the regulation of desquamation through its inhibitory activity towards proteases of the chymotrypsin family, notably KLK7.

Update on peptidylarginine deiminases and deimination in skin physiology and severe human diseases.

Deimination (or citrullination) is a recently described post-translational modification, but its consequences are not yet well understood. It is catalysed by peptidylarginine deiminases (PADs). These enzymes transform arginyl residues involved in a peptidyl link into citrullyl residues in a calcium-dependent manner.

Peptidyl arginine deiminase type 2 (PAD-2) and PAD-4 but not PAD-1, PAD-3, and PAD-6 are expressed in rheumatoid arthritis synovium in close association with tissue inflammation.

Objective: Autoantibodies to citrullinated proteins (ACPAs) are specific for rheumatoid arthritis (RA) and probably are involved in its pathophysiology. Citrullyl residues, posttranslationally generated by peptidyl arginine deiminase (PAD), are indispensable components of ACPA-targeted epitopes. The aim of this study was to identify which PAD isotypes are expressed in the synovial tissue (ST) of patients with RA and are involved in the citrullination of fibrin, the major synovial target of ACPAs.

Large-scale identification of human genes implicated in epidermal barrier function.

Background: During epidermal differentiation, keratinocytes progressing through the suprabasal layers undergo complex and tightly regulated biochemical modifications leading to cornification and desquamation. The last living cells, the granular keratinocytes (GKs), produce almost all of the proteins and lipids required for the protective barrier function before their programmed cell death gives rise to corneocytes. We present here the first analysis of the transcriptome of human GKs, purified from healthy epidermis by an original approach.

A novel protease inhibitor of the alpha2-macroglobulin family expressed in the human epidermis.

In the course of a large scale analysis of late-expressed genes in the human epidermis, we identified a new member of the alpha(2)-macroglobulin (alpha2M) protease inhibitor family, A2ML1 (for alpha(2)-macroglobulin-like 1). Like A2M and PZP, A2ML1 is located on chromosome 12p13.31.

A family based study shows no association between rheumatoid arthritis and the PADI4 gene in a white French population.

Background: Autoantibodies to citrullinated proteins (ACPA) are considered a specific marker for rheumatoid arthritis. Peptidylarginine deiminase (PAD) is the enzyme that converts arginyl into citrullyl residues; different isoforms of the enzyme are expressed in mammals. It has been suggested that the PADI4 gene may contribute to genetic susceptibility to rheumatoid arthritis, but conflicting results have been obtained in different populations.

Degradation of corneodesmosome proteins by two serine proteases of the kallikrein family, SCTE/KLK5/hK5 and SCCE/KLK7/hK7.

Corneodesmosin (CDSN), desmoglein 1 (DSG1), and desmocollin 1 (DSC1) are adhesive proteins of the extracellular part of the corneodesmosomes, the junctional structures that mediate corneocyte cohesion. The degradation of these proteins at the epidermis surface is necessary for desquamation. Two serine proteases of the kallikrein family synthesized as inactive precursors have been implicated in this process: the stratum corneum chymotryptic enzyme (SCCE/KLK7/hK7) and the stratum corneum tryptic enzyme (SCTE/KLK5/hK5).

A 4.2 kb upstream region of the human corneodesmosin gene directs site-specific expression in hair follicles and hyperkeratotic epidermis of transgenic mice.

Corneodesmosin (CDSN) is a desmosomal protein expressed in the epidermis during the late stages of differentiation and in the inner root sheath of hair follicles. The homophilic adhesive properties of the protein suggest that it reinforces keratinocyte cohesion in the upper layers of the epidermis (stratum granulosum and stratum corneum). In this study, we analyzed the expression of the CDSN gene in 16 human tissues.

Hypotrichosis simplex of the scalp is associated with nonsense mutations in CDSN encoding corneodesmosin.

We have identified nonsense mutations in the gene CDSN (encoding corneodesmosin) in three families suffering from hypotrichosis simplex of the scalp (HSS; OMIM 146520). CDSN, a glycoprotein expressed in the epidermis and inner root sheath (IRS) of hair follicles, is a keratinocyte adhesion molecule. Truncated CDSN aggregates were detected in the superficial dermis and at the periphery of hair follicles.

cDNA cloning, gene organization and expression analysis of human peptidylarginine deiminase type I.

Peptidylarginine deiminases (PADs) catalyse a post-translational modification of proteins through the conversion of arginine residues into citrullines. The existence of four isoforms of PAD (types I, II, III and IV) encoded by four different genes, which are distinct in their substrate specificities and tissue-specific expression, was reported in rodents. In the present study, starting from epidermis polyadenylated RNA, we cloned by reverse transcriptase-PCR a full-length cDNA encoding human PAD type I.

Corneodesmosin, a component of epidermal corneocyte desmosomes, displays homophilic adhesive properties.

Corneodesmosomes, the modified desmosomes of the uppermost layers of the epidermis, play an important role in corneocyte cohesion. Corneodesmosin is a secreted glycoprotein located in the corneodesmosomal core and covalently linked to the cornified envelope of corneocytes. Its glycine- and serine-rich NH(2)-terminal domain may fold to give structural motifs similar to the glycine loops described in epidermal cytokeratins and loricrin and proposed to display adhesive properties.

Corneodesmosin expression in psoriasis vulgaris differs from normal skin and other inflammatory skin disorders.

Corneodesmosin (Cdsn) is a late differentiation epidermal glycoprotein putatively involved in keratinocyte adhesion. The Cdsn gene lies within the susceptibility region on chromosome 6p21.3 (PSORS1) for psoriasis, a common chronic disfiguring skin disease.

Refined characterization of corneodesmosin proteolysis during terminal differentiation of human epidermis and its relationship to desquamation.

Corneodesmosin is a putative adhesion glycoprotein located in the extracellular part of the desmosomes in the upper layers of the epidermis. Synthesized by granular keratinocytes as a 52-56-kDa protein, corneodesmosin is progressively proteolysed during corneocyte maturation. This processing is a prerequisite for desquamation.

Identification of six novel polymorphisms in the human corneodesmosin gene.

Psoriatic epidermis is characterised by a defective differentiation program leading to an abnormal permeability barrier and impaired desquamation. The corneodesmosin gene (CDSN) or "S" gene is a strong candidate in psoriasis susceptibility, due first to its genomic position ("S" gene, 160 kb telomeric to HLA-C) and second to its expression and function in the epidermis. Moreover, an association between CDSN and psoriasis vulgaris was recently shown in Caucasian populations.

Interconnections between E2-dependent regulation of cell cycle progression and apoptosis in MCF-7 tumors growing on nude mice.

Growth of human breast adenocarcinoma MCF-7 cells as a tumor on nude mice is dependent on estrogen. It has been shown that estrogen withdrawal (EW) induces a partial regression of the tumor via an inhibition of cell proliferation and an induction of apoptosis. We investigated in this in vivo model the underlying molecular mechanisms of the hormone-dependent regulation of cell cycle machinery and apoptosis.

Expression cloning of human corneodesmosin proves its identity with the product of the S gene and allows improved characterization of its processing during keratinocyte differentiation.

In human epidermis and other cornified squamous epithelia, corneodesmosin is located in the desmosomes of the upper living layers, and in related structures of the cornified layers, the corneodesmosomes. During maturation of the cornified layers, the protein undergoes a series of cleavages, thought to be a prerequisite of desquamation. Partial amino acid sequencing of corneodesmosin fragments suggested that it is related to the product of the S gene, previously identified in the human major histocompatibility complex.

Characterization and purification of human corneodesmosin, an epidermal basic glycoprotein associated with corneocyte-specific modified desmosomes.

Using monoclonal antibodies, we identified a new protein in mammalian epidermis, which we called corneodesmosin. It is located in the extracellular part of the modified desmosomes in the cornified layer of the tissue, and its proteolysis (from 52-56 to 33 kDa) is thought to be a major prerequisite of desquamation. We have now further characterized human corneodesmosin.

Corneodesmosin, a corneodesmosome-specific basic protein, is expressed in the cornified epithelia of the pig, guinea pig, rat, and mouse.

Proteolysis of corneodesmosin, a 52- to 56-kDa basic protein located in the extracellular part of the modified desmosomes (corneodesmosomes) of human cornified epithelia, is thought to be a key event of desquamation. Three monoclonal antibodies specific for human corneodesmosin were used to search for the expression of the protein in other mammals. Cryosections of pig, guinea pig, rat, and mouse cornified tissues and proteins sequentially extracted from the corresponding epithelia were analyzed by immunofluorescence and immunoblotting, respectively.

Overexpression of vascular endothelial growth factor induces cell transformation in cooperation with fibroblast growth factor 2.

Vascular endothelial growth factor (VEGF) is a family of homodimeric proteins produced from a single gene by alternative splicing of the VEGF transcript. VEGF induces in vivo angiogenesis and vascular permeability. We have recently demonstrated that VEGF is an autocrine growth factor for retinal pigment epithelial (RPE) cells.