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• W2604245548 abstract "Renewal of the stratum corneum is ensured by a finely tuned network of proteases and their endogenous inhibitors, in which kallikrein-related peptidases (KLKs) play key roles. In skin, KLKs operate in cascades (Pampalakis and Sotiropoulou, 2007Pampalakis G. Sotiropoulou G. Tissue kallikrein proteolytic cascade pathways in normal physiology and cancer.Biochim Biophys Acta. 2007; 1776: 22-31PubMed Google Scholar) in crosstalk with other proteases such as metalloproteinases and caspase 14 (de Veer et al., 2014de Veer S.J. Furion L. Harris J.M. Hovnanian A. Proteases: common culprits in human skin disorders.Trends Mol Med. 2014; 20: 166-178Abstract Full Text Full Text PDF PubMed Scopus (75) Google Scholar). Specifically, KLK5, 6, 7, and 14 are expressed in the epidermis and are involved in the proteolytic cleavage of corneodesmosomal proteins (Borgoňo et al., 2007Borgoňo C. Michael I.P. Komatsu N. Jayakumar A. Kapadia R. Clayman G.L. et al.A potential role for multiple tissue kallikrein serine proteases in epidermal desquamation: regulation by lympho-epithelial Kazal-type inhibitor and digestion of desmoglein 1.J Biol Chem. 2007; 282: 3640-3652Crossref PubMed Scopus (224) Google Scholar, Caubet et al., 2004Caubet C. Jonca N. Brattsand M. Guerrin M. Bernard D. Schmidt R. et al.Degradation of corneodesmosome proteins by two serine proteases of the kallikrein family, SCTE/KLK5/hK5 and SCCE/KLK7/hK7.J Invest Dermatol. 2004; 122: 1235-1244Abstract Full Text Full Text PDF PubMed Scopus (418) Google Scholar). Unopposed activities of KLK proteases in lympho-epithelial Kazal-type-related inhibitor-deficient epidermis (due to SPINK5 mutations) underlie the severe pathological overdesquamation and inflammation observed in Netherton syndrome (Furio et al., 2015Furio L. Pampalakis G. Michael I.P. Nagy A. Sotiropoulou G. Hovnanian A. KLK5 inactivation reverses cutaneous hallmarks of Netherton syndrome.PLoS Genet. 2015; 11: e1005389Crossref PubMed Scopus (66) Google Scholar, Komatsu et al., 2008Komatsu N. Saijoh K. Jayakumar A. Clayman G.L. Tohyama M. Suga Y. et al.Correlation between SPINK5 gene mutations and clinical manifestations in Netherton syndrome patients.J Invest Dermatol. 2008; 128: 1148-1159Abstract Full Text Full Text PDF PubMed Scopus (81) Google Scholar). Also, abnormally elevated expression and activities of KLKs have been observed in the epidermis of patients with peeling skin syndrome-type B (due to mutations in CDSN) (Komatsu et al., 2006Komatsu N. Suga Y. Saijoh K. Liu A.C. Khan S. Mizuno Y. et al.Elevated human tissue kallikrein levels in the stratum corneum and serum of peeling skin syndrome-type B patients suggests an over-desquamation of corneocytes.J Invest Dermatol. 2006; 126: 2338-2342Abstract Full Text Full Text PDF PubMed Scopus (56) Google Scholar; Oji et al., 2010Oji V. Eckl K.M. Aufenvenne K. Nätebus M. Tarinski T. Ackermann K. et al.Loss of corneodesmosin leads to severe skin barrier defect, pruritus, and atopy: unraveling the peeling skin disease.Am J Hum Genet. 2010; 87: 274-281Abstract Full Text Full Text PDF PubMed Scopus (170) Google Scholar). On the other hand, KLK5 and 7 activities are diminished in harlequin ichthyosis epidermis (Thomas et al., 2009Thomas A.C. Tattersall D. Norgett E.E. O’Toole E.A. Kelsell D.P. Premature terminal differentiation and a reduction in specific proteases associated with loss of ABCA12 in Harlequin ichthyosis.Am J Pathol. 2009; 174: 970-978Abstract Full Text Full Text PDF PubMed Scopus (47) Google Scholar). Thus, deregulated proteolysis seems to be a feature of skin pathologies of distinct genetic causes, which are nonetheless all characterized by a defective epidermal barrier. Thus, certain KLKs have been targeted therapeutically in different diseases including skin diseases (Sotiropoulou and Pampalakis, 2012Sotiropoulou G. Pampalakis G. Targeting the kallikrein-related peptidases for drug development.Trends Pharmacol Sci. 2012; 33: 623-634Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar). Acral peeling skin syndrome (APSS) is a rare autosomal recessive skin disorder characterized by painless, superficial blistering and peeling of the hands and feet. Very little is currently known on the pathogenetic mechanisms underlying APSS disease except that it is caused by mutations in the TG5 gene encoding transglutaminase 5 (TG5) (Cassidy et al., 2005Cassidy A.J. van Steensel M.A. Steijlen P.M. van Geel M. van der Velden J. Morley S.M. et al.A homozygous missense mutation in TGM5 abolishes epidermal transglutaminase 5 activity and causes acral peeling skin syndrome.Am J Hum Genet. 2005; 77: 909-917Abstract Full Text Full Text PDF PubMed Scopus (105) Google Scholar, Pigors et al., 2012Pigors M. Kiritsi D. Cobzaru C. Schwieger-Briel A. Suárez J. Faletra F. et al.TGM5 mutations impact epidermal differentiation in acral peeling skin syndrome.J Invest Dermatol. 2012; 132: 2422-2429Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar). TG5 is responsible for introducing γ-glutamyl-ε-lysine isopeptide bonds into the structural proteins (e.g., loricrin, involucrin, small proline-rich proteins) of the cornified envelope and corneocyte (Candi et al., 2005Candi E. Schmidt R. Melino G. The cornified envelope: a model of cell death in the skin.Nat Rev Mol Cell Biol. 2005; 6: 328-340Crossref PubMed Scopus (1267) Google Scholar). Still, it is not clear which proteins exactly are crosslinked by TG5 in vivo and why peeling only occurs in acral regions, especially, considering the fact that TG5 is expressed in the epidermis of the entire body (Van der Velden et al., 2015Van der Velden J.J. van Geel M. Nellen R.G. Jonkman M.F. McGrath J.A. Nanda A. et al.Novel TGM5 mutations in acral peeling skin syndrome.Exp Dermatol. 2015; 24: 285-289Crossref PubMed Scopus (10) Google Scholar). It has been shown that SPINK6 is crosslinked in the epidermis by TG1 and 3, probably as a protective mechanism from KLK-related peptidases, which are involved in desquamation (J1 et al., 2013Fischer J. Koblyakova Y. Latendorf T. Wu Z. Meyer-Hoffert U. Cross-linking of SPINK6 by transglutaminases protects from epidermal proteases.J Invest Dermatol. 2013; 133: 1170-1177Abstract Full Text Full Text PDF PubMed Scopus (25) Google Scholar); thus, it seems likely that TG5 is also involved in this process. Another suspected target of TG5 is SPINK9, which is mainly expressed at palmoplantar sites, explaining the presence of only palmoplantar peeling. Because APSS is a desquamating disorder, we hypothesized that aberrant epidermal proteolysis could be the underlying cause of this pathognomonic feature. We analyzed the overall proteolytic activities in the epidermis of patients with APSS and normal donors by in situ zymography using fluorescently quenched gelatin, casein, and elastin substrates to map different protease specificities, and found aberrantly elevated proteolysis in APSS. Skin biopsies from patients with homozygous TG5 mutations (verified by DNA sequencing) were used following written informed consents and the protocol was approved by the University of Freiburg (Kiritsi et al., 2010Kiritsi D. Cosgarea I. Franzke C.W. Schumann H. Oji V. Kohlhase J. et al.Acral peeling skin syndrome with TGM5 gene mutations may resemble epidermolysis bullosa simplex in young individuals.J Invest Dermatol. 2010; 130: 1741-1746Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar, Pigors et al., 2012Pigors M. Kiritsi D. Cobzaru C. Schwieger-Briel A. Suárez J. Faletra F. et al.TGM5 mutations impact epidermal differentiation in acral peeling skin syndrome.J Invest Dermatol. 2012; 132: 2422-2429Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar). Caseinolytic and gelatinolytic activities were highly increased at the sites of peeling and correlated with disease severity in that patients with more pronounced desquamation exhibited higher levels of epidermal proteolysis (Figure 1a and b and Supplementary Figure S1 online). Gelatinolytic activities were highly induced in APSS epidermis, and were mainly localized in the stratum corneum, whereas caseinolytic activities were detected throughout the epidermis with a preference for the lower layers. These spatially distinct proteolytic patterns reflect the function of different protease specificities along epidermal layers. Elastinolytic activities did not differ significantly in APSS compared with healthy skin, although the total elastinolytic activity could be slightly higher considering that APSS epidermis is thicker (Figure 1c). Elevated proteolysis may be caused by either increased expression of proteases or lack of their specific endogenous inhibitors. The expression of 13 major epidermal proteases was quantified in patients with APSS and in normal skin (Supplementary Figure S2 online). Of all proteases tested, ADAM17, MMP2, and MMP9 metalloproteinases were upregulated justifying the elevated gelatinolytic activity. Overall, protease mRNA expression was reduced in APSS as KLK6, 7, 14 and matriptase were markedly reduced, and immunohistochemistry staining showed consistently lower KLK6 protein in all patients (Supplementary Figure S3 online). Thus, the observed aberrantly high proteolytic activity cannot be explained by elevated mRNA expression. Furthermore, in APSS, some proteases could be reduced at the protein level as shown here for KLK5 (Supplementary Figure S3) for which we observed unaltered mRNA levels (Supplementary Figure S2). Interestingly, key protease inhibitors such as lympho-epithelial Kazal-type-related inhibitor (SPINK5) and cystatin M/E (CST6) were absent in APSS epidermis (Figure 2a and Supplementary Figure S4 online), and this could account for high activities of KLKs and other serine proteases and cathepsins, respectively. Nonetheless, endogenous protease inhibitors were not uniformly reduced or absent because TIMP1, cystatin B, and elafin were unaltered at the mRNA level. In addition, TIMP2 expression was high in the patient with mild desquamation but absent in the patient with pronounced desquamation.Figure 2Expression of endogenous protease inhibitors in APSS skin. (a) Εndogenous inhibitors normally expressed in epidermis are deregulated in APSS. Protease inhibitor mRNA expression was quantified by RT-qPCR using 20 ng cDNA as template and two-step cycling conditions (95 °C for denaturation, 60 °C for annealing and extension, for 45 cycles). Gene-specific primers were designed or obtained from Qiagen (Hilden, Germany) (Supplementary Table S1 online). The identity of amplified PCR products was confirmed by DNA sequencing (VBC, Vienna, Austria). The control depicts the mean expression of four normal samples. (b) Abnormally high epidermal proteolysis is associated with enhanced degradation of desmoglein 1 (DSG1). DSG1 expression was analyzed by IHC using an anti-DSG1 antibody (H-290: sc-20114; Santa Cruz, Heidelberg, Germany) at dilution 1:300. Scale bar: 200 μm. Comparisons were made with the h score. The epidermis is shown on the top. The black dashed line indicates the dermis-epidermis junction. Representative image of one of three different controls is shown. APSS, acral peeling skin syndrome; IHC, immunohistochemistry; RT-qPCR, quantitative reverse transcription PCR.View Large Image Figure ViewerDownload Hi-res image Download (PPT) Cumulatively, the web of proteases and endogenous protease inhibitors that are involved in epidermal desquamation, proliferation, and differentiation is deregulated in APSS epidermis, and this is likely underlying the disease phenotype. Figure 2b shows that DSG1 immunohistochemistry staining correlates inversely with proteolysis levels in APSS skin. DSG1 is a major component of desmosomes, and its regulated degradation by proteases is required for physiological skin desquamation. Thus, enhanced proteolysis in APSS may be linked to altered epidermal structure and function. Furthermore, deregulated protease inhibitors in the APSS epidermis may be linked to the function of transglutaminases because transglutaminases have been shown to crosslink structural proteins but also to anchor protease inhibitors, such as cystatin M/E and SKALP/elafin (PI3), to the stratum corneum (Zeeuwen et al., 2001Zeeuwen P.L. Van Vlijmen-Willems I.M. Jansen B.J. Sotiropoulou G. Curfs J.H. Meis J.E. et al.Cystatin M/E expression is restricted to differentiated epidermal keratinocytes and sweat glands: a new skin-specific proteinase inhibitor that is a target for cross-linking by transglutaminases.J Invest Dermatol. 2001; 116: 693-701Abstract Full Text Full Text PDF PubMed Scopus (90) Google Scholar). When TG5 is mutated, anchoring of protease inhibitors may not occur efficiently, which could, in turn, compromise their inhibitory activity. Thus, the lack of anchoring of the elastase inhibitor elafin could explain the unchanged elastinolytic activity in APSS (Figure 1). In patients with APSS carrying TG5 missense mutations, the TG5 mRNA levels were unaltered and comparable to control skin (Supplementary Figure S5a online); however, transglutaminase activity was decreased in APSS epidermis and this decrease correlated nicely with disease severity (Supplementary Figure S5b). Therefore, although patients with APSS mostly carry missense mutations (Pigors et al., 2012Pigors M. Kiritsi D. Cobzaru C. Schwieger-Briel A. Suárez J. Faletra F. et al.TGM5 mutations impact epidermal differentiation in acral peeling skin syndrome.J Invest Dermatol. 2012; 132: 2422-2429Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar), diminished TG5 activity accounts for the observed effects in the epidermal proteolysis. To our knowledge, our findings reveal previously unreported roles of TG5 in skin homeostasis. We show that the APSS epidermis is characterized by aberrantly elevated proteolytic activities resulting in enhanced degradation of DSG1, thus, compromising skin barrier function. Whether the increased proteolysis is a secondary effect due to epidermal barrier dysfunction or the inability of inhibitors to crosslink into the stratum corneum remains to be elucidated. Epidermal overproteolysis appears a uniform feature of overdesquamating skin diseases. Although originally thought to be exceptionally rare, recent studies revealed that APSS is under-reported and widely misdiagnosed (Kiritsi et al., 2010Kiritsi D. Cosgarea I. Franzke C.W. Schumann H. Oji V. Kohlhase J. et al.Acral peeling skin syndrome with TGM5 gene mutations may resemble epidermolysis bullosa simplex in young individuals.J Invest Dermatol. 2010; 130: 1741-1746Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar, Szczecinska et al., 2014Szczecinska W. Nesteruk D. Wertheim-Tysarowska K. Greenblatt D.T. Baty D. Browne F. et al.Under-recognition of acral peeling skin syndrome: 59 new cases with 15 novel mutations.Br J Dermatol. 2014; 171: 1206-1210Crossref PubMed Scopus (20) Google Scholar). Deciphering the underlying molecular mechanisms is indispensable for the designing of new therapeutic approaches for this disease. The authors state no conflict of interest. The excellent technical support by Ioannis Athanasiou and Kaethe Thoma is gratefully acknowledged. This work was supported by the grant of the German Research Foundation DFG (grant 1795/1-1) to DK. The contribution of Prof. Cristina Has (Head of the Molecular Dermatology, University of Freiburg) and Prof. Jürgen Kohlhase (Center for Human Genetics Freiburg) for the identification of the patients’ mutations is greatly acknowledged. Download .pdf (1.28 MB) Help with pdf files Supplementary Data" @default.
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• W2604245548 title "Enhanced Proteolytic Activities in Acral Peeling Skin Syndrome: A Role of Transglutaminase 5 in Epidermal Homeostasis" @default.
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