Stratum Corneum Moisturization at the Molecular Level

Rawlings, A. V.; Scott, Ian; Harding, Clive R.; Bowser, P. A.

doi:10.1111/1523-1747.ep12398620

Cited by 413 publications

(358 citation statements)

References 110 publications

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“…Because the amino acid composition of FLG2 B-type repeats is similar to that of FLG, breakdown of FLG2 into free amino acids by other proteases, including caspase 14, may contribute to the NMF components. Until now, FLG has been considered as the only protein at the origin of the NMF and therefore responsible for stratum corneum hydration, flexibility, and UV protection (21,40,41). Based on our findings, FLG2 could contribute to stratum corneum hydration and barrier functions along with FLG.…”

Section: Discussionsupporting

confidence: 53%

“…Numerous proteases, including calpain 1 (22), furin (36), profilaggrin endoproteinase 1 (37), matriptase (38), channel-activating serine protease 1 (39), and elastase-2 (40), have been identified as being involved either directly or indirectly in the profilaggrin processing to FLG monomers, whereas calpain 1, caspase-14, and bleomycin hydrolase (23) are required for further proteol- ysis of FLG monomers into smaller peptides and free amino acids. The latter are the major components of the so-called natural moisturizing factor (NMF), the main function of which is to contribute to water retention, flexibility of the stratum corneum, and UV protection (21,41,42). We speculated that the same enzymes could be involved in the processing of FLG2.…”

Section: Discussionmentioning

confidence: 99%

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

Hsu

Henry

Raymond

et al. 2011

Journal of Biological Chemistry

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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Section: Discussionsupporting

confidence: 53%

Section: Discussionmentioning

confidence: 99%

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

Hsu

Henry

Raymond

et al. 2011

Journal of Biological Chemistry

113

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“…Filaggrin not only has the function of bundling keratins in corneocytes but also subsequently is degraded to modified free amino acids in s. corneum. These modified amino acids are highly hygroscopic and essential for maintaining osmolarity and flexibility of the epidermis (Rawlings et al, 1994;Elias, 2004). Delay in full filaggrin processing and subsequent shortage in hygroscopic amino acid residues in corneocytes could explain the thinness and fragility of corneocytes seen in Cx43K258stop epidermis.…”

Section: Discussionmentioning

confidence: 99%

Defective Epidermal Barrier in Neonatal Mice Lacking the C-Terminal Region of Connexin43

Maass

Ghanem

Kim

et al. 2004

MBoC

127

145

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“…The CE provides a relatively-inflexible, mechanically-resistant barrier. However, as the water content of the SC drops in the mid-to-outer SC, FLG detaches from the CE, and the C-terminal portion of FLG is proteolyzed into its constituent amino acids, followed by their deimination into polycarboxylic acids (=natural moisturizing factors, NMF) 36,37 , such as pyrrolidine carboxylic acid and trans-urocanic acid (t-UCA) 38 . These metabolites, in turn, act as osmolytes, drawing water into corneocytes, thereby accounting in large part for corneocyte hydration.…”

Section: Relationship Of Ichthyosis Vulgaris To Atopic Dermatitismentioning

confidence: 99%

Therapeutic Implications of a Barrier-based Pathogenesis of Atopic Dermatitis

Elias

2010

Ann Dermatol

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In this review, I first provide relevant background information about normal epidermal barrier structure and function. I then update recent information about how inherited defects in either filaggrin and/or in the serine protease inhibitor, lymphoepithelial Kazal-type inhibitor 1, converge to stimulate the development of atopic dermatitis (AD). Next I explain the multiple mechanisms whereby a primary barrier abnormality in AD can lead to inflammation. Furthermore, I explore how certain acquired stressors, such as a reduced external humidity, high pH soaps/surfactants, psychological stress, as well as secondary Staphylococcus aureus infections initiate or further aggravate AD. Finally, and most importantly, I compare various therapeutic paradigms for AD, highlighting the risks and benefits of glucocorticoids and immunomodulators vs. corrective, lipid replacement therapy. (Ann Dermatol 22(3) 245∼254, 2010)

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Stratum Corneum Moisturization at the Molecular Level

Cited by 413 publications

References 110 publications

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

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

Defective Epidermal Barrier in Neonatal Mice Lacking the C-Terminal Region of Connexin43

Therapeutic Implications of a Barrier-based Pathogenesis of Atopic Dermatitis

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