Peptidylarginine deiminases and deimination in biology and pathology: Relevance to skin homeostasis

Chavanas, Stéphane; Méchin, Marie-Claire; Nachat, Rachida; Adoue, Véronique; Coudane, Fanny; Serre, Guy; Simon, Michel

doi:10.1016/j.jdermsci.2006.07.004

Cited by 73 publications

(60 citation statements)

References 61 publications

(69 reference statements)

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“…Messenger RNAs encoding PAD 4 and 6 are not detected in the normal tissue. Using anti-peptide antibodies specific for each isoform, we have confirmed this result at the protein level (Nachat et al, 2005a;Chavanas et al, 2006). Moreover, PAD1 is localized in the cytoplasm of keratinocytes throughout the whole human epidermis, with a higher expression in the granular layer, and in the corneocytes.…”

Section: Peptidylarginine Deiminases In the Epidermissupporting

confidence: 67%

Peptidylarginine Deiminases and Protein Deimination in Skin Physiopathology

Ying¹,

Simon²,

Serre³

et al. 2012

Psoriasis - A Systemic Disease

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Section: Peptidylarginine Deiminases In the Epidermissupporting

confidence: 67%

Peptidylarginine Deiminases and Protein Deimination in Skin Physiopathology

Ying¹,

Simon²,

Serre³

et al. 2012

Psoriasis - A Systemic Disease

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“…We demonstrated that at least one of them was modified by PAD1, a similar Arg residue being located in all B-type repeats in a conserved position just before a calpain 1 cleavage site. Based on previous studies (32,47,48), we believe that deimination of FLG2 alters its spatial conformation and consequently facilitates its proteolysis. The three-dimensional structure of neither FLG2 nor FLG is known; therefore, it is currently not possible to test this hypothesis in silico.…”

Section: Discussionmentioning

confidence: 77%

Deimination of Human Filaggrin-2 Promotes Its Proteolysis by Calpain 1

Hsu

Henry

Raymond

et al. 2011

Journal of Biological Chemistry

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113

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Filaggrin-2 (FLG2), a member of the S100-fused type protein family, shares numerous features with filaggrin (FLG), a key protein implicated in the epidermal barrier functions. Both display a related structural organization, an identical pattern of expression and localization in human epidermis, and proteolytic processing of a large precursor. Here, we tested whether FLG2 was a substrate of calpain 1, a calcium-dependent protease directly involved in FLG catabolism. In addition, deimination being critical for FLG degradation, we analyzed whether FLG2 deimination interfered with its proteolytic processing. With this aim, we first produced a recombinant form of FLG2 corresponding to subunits B7 to B10 fused to a COOH-terminal His tag. Incubation with calpain 1 in the presence of calcium induced a rapid degradation of the recombinant protein and the production of several peptides, as shown by Coomassie Blue-stained gels and Western blotting with anti-FLG2 or anti-His antibodies. MALDI-TOF mass spectrometry confirmed this result and further evidenced the production of non-immunoreactive smaller peptides. The degradation was not observed when a calpain 1-specific inhibitor was added. The calpain cleavage sites identified by Edman degradation were regularly present in the B-type repeats of FLG2. Moreover, immunohistochemical analysis of normal human skin revealed colocalization of FLG2 and calpain 1 in the upper epidermis. Finally, the FLG2 deiminated by human peptidylarginine deiminases was shown to be more susceptible to calpain 1 than the unmodified protein. Altogether, these data demonstrate that calpain 1 is essential for the proteolytic processing of FLG2 and that deimination accelerates this process.In the epidermis, the program of keratinocyte terminal differentiation is an oriented process during which cells of the basal layer undergo a series of metabolic and structural changes throughout their migration to the surface of the tissue. The stratum corneum, the outermost layer of the epidermis, is formed by the stacking of so-called corneocytes, the end products of the process. The stratum corneum functions as an effective barrier between the body and its outside environment, limiting skin dehydration and preventing the penetration of outside pathogens, UV radiation, and exogenous chemicals. It also contributes to mechanical protection of the body. So that this function can be achieved, peculiar structures are formed, such as the cornified cell envelope, a resistant and insoluble protein shell that replaces the plasma membrane, and the intracorneocyte fibrous matrix made by the aggregation of keratin intermediate filaments.

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“…However, the sum of the three concentrations (Arg + Cit + Orn) is much more reproducible, and the collective distribution is quite similar to that of the individual compounds in groups A and B. It is known that ornithine is derived from the breakdown of arginine (by arginase-1), and that citrulline is the degradation product of arginine by nitric oxide synthase (NOS) (34) and peptidylarginine deiminases (PAD1 and PAD3) (35). As a result, it is possible that, while variability in enzyme activities between individuals may lead to marked differences in the individual levels of Arg, Cit and Orn, the sum of the amounts of the three compounds may be relatively constant across subjects as has in fact been observed.…”

Section: Discussionmentioning

confidence: 99%

Characterisation of Skin Barrier Function Using Bioengineering and Biophysical Techniques

Yang

Guy

2014

Pharm Res

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Purpose: To characterise skin barrier function in vivo at two distinct anatomic sites using minimally invasive bioengineering and biophysical tools.Methods: In healthy human volunteers, the quantities of stratum corneum (SC) per unit area of skin on the forearm and forehead were quantified by gravimetric and imaging techniques. Organisation of the SC intercellular lipids was evaluated as a function of position using attenuated total reflectance infrared spectroscopy (ATR-IR). The constituents of natural moisturising factor (NMF) were extracted from tape-stripped samples of the SC and by reverse iontophoresis; 21 components were identified and quantified by liquid chromatography with mass spectrometric detection.Results: SC was quantified more accurately by imaging and was significantly thinner on the forehead than on the forearm. Intercellular lipids were more disordered near the skin surface at both sites; however, throughout forearm SC, the lipids were substantially better organised than those in the forehead. Compositionally, the NMF from forearm and forehead SC was similar, but the total amount extractable from the forehead was smaller.Conclusion: Taken together, the bioengineering and biophysical techniques employed demonstrate, in a complementary, objective and quantitative fashion, that SC barrier function on the forehead is less competent than that on the forearm.Keywords: stratum corneum, skin barrier function natural moisturizing factor (NMF), reverse iontophoresis, infrared spectroscopy 3 Abbreviations IntroductionNatural moisturizing factor (NMF) is a collection of water-soluble, low molecular weight compounds found in the stratum corneum (SC). Functionally, it allows the SC to retain water against the dehydrating action of external environment and thus plays a key role in skin hydration (1). NMF is composed primarily of free amino acids (AAs) and amino acid derivatives that are derived from filaggrin. Filaggrin is synthesized from profilaggrin, an approximately 500-kDa insoluble protein, consisting of 10 to 12 repeating filaggrin units (2,3). During the transition of the mature granular cell into a corneocyte, rapid dephosphorylation of pro-filaggrin occurs, yielding filaggrin (3). As corneocytes proceed upwards through the SC, deiminiation and complete proteolysis of filaggrin yields the main components of NMF, specifically, (a) free hygroscopic amino acids (mainly Ser, Ala, Arg, Gly, Pro and His (4)), and (b) the following amino acid derivatives: pyrollidone carboxylic acid (PCA) formed by cyclisation of glutamine (5), trans-urocanic acid (UCA) synthesised from histidine (3), and ornithine (Orn) and citruline (Cit), which are degradation products of arginine (6).Presently, a filaggrin mutation is considered to be the strongest genetic risk factor for atopic dermatitis (AD) (7-10). As a result of this mutation, lower levels of NMF are generated in atopic skin and this is thought to contribute to an impaired barrier function (4, 11). Furthermore, a reduced NMF level has also been reported i...

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Peptidylarginine deiminases and deimination in biology and pathology: Relevance to skin homeostasis

Cited by 73 publications

References 61 publications

Peptidylarginine Deiminases and Protein Deimination in Skin Physiopathology

Peptidylarginine Deiminases and Protein Deimination in Skin Physiopathology

Deimination of Human Filaggrin-2 Promotes Its Proteolysis by Calpain 1

Characterisation of Skin Barrier Function Using Bioengineering and Biophysical Techniques

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