Cathepsin D, but not cathepsin E, degrades desmosomes during epidermal desquamation

Igarashi, Seiji; Tajima, Toshihiro; Yasuda, Yoh; Uchiwa, Hideyo; Hayashi, Seiichi; Brysk, Henry; Robinson, JM; Yamamoto, Kazuo; Brysk, Miriam M.; Horikoshi, Tsutomu

doi:10.1111/j.1365-2133.2004.06061.x

Cited by 54 publications

(41 citation statements)

References 19 publications

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“…26 -28 CTSD also has a role in epidermal desquamation through corneodesmosome degradation. 29 CTSD is activated by ceramides derived from acid sphingomyelinase. 30 The fact that ceramides may be significantly reduced/absent from the SC of HI skin could additionally hinder the role of CTSD during desquamation.…”

Section: Discussionmentioning

confidence: 99%

Premature Terminal Differentiation and a Reduction in Specific Proteases Associated with Loss of ABCA12 in Harlequin Ichthyosis

Thomas

Tattersall

Norgett

et al. 2009

The American Journal of Pathology

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One of the primary functions of skin is to form a defensive barrier against external infections and water loss. Disrupted barrier function underlies the most severe and often lethal form of recessive congenital ichthyosis, harlequin ichthyosis (HI). HI is associated with mutations in the gene that encodes the ABC transporter protein, ABCA12. We have investigated the morphological and biochemical alterations associated with abnormal epidermal differentiation and barrier formation in HI epidermis. An in vitro model of HI skin using human keratinocytes retrovirally transduced with shRNA targeting ABCA12 in a three-dimensional , organotypic co-culture (OTCC) system has also been developed. A robust reduction in ABCA12 expression had a dramatic effect on keratinocyte differentiation and morphology comparable with that observed in HI skin, including a thicker epidermis and abnormal lipid content with a reduction in nonpolar lipids. As seen in HI epidermis, proteins that are normally expressed in late differentiation were highly dysregulated in the ABCA12-ablated OTCC system. These proteins were expressed in the stratum basale and also in the stratum spinosum, indicative of a premature terminal differentiation phenotype. Expression of the proteases kallikrein 5 and cathepsin D was dramatically reduced in both HI epidermis and the OTCC model. These data suggest that ABCA12 is a key molecule in regulating keratinocyte differentiation and transporting specific proteases associated with desquamation.

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Section: Discussionmentioning

confidence: 99%

Premature Terminal Differentiation and a Reduction in Specific Proteases Associated with Loss of ABCA12 in Harlequin Ichthyosis

Thomas

Tattersall

Norgett

et al. 2009

The American Journal of Pathology

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“…This observation appeared to be reasonable considering that the major sorting mechanism of those hydrolases to lysosome is by the mannose 6-phosphate pathway (24). In the epidermis, enzymes of lysosomes and lamellar granules are present also in the extracellular (25). Lamellar granules (LGs), which are considered to be lysosome-related organelles (8), are organelles present in the cytoplasm of cells in the granular layer and account for about 10% of the volume of the granular cell cytosol (26).…”

Section: Table I Observed Signals Of Aowr-labeled Oligosaccharides Rementioning

confidence: 99%

High Throughput Quantitative Glycomics and Glycoform-focused Proteomics of Murine Dermis and Epidermis

Uematsu

Furukawa

Nakagawa

et al. 2005

Molecular & Cellular Proteomics

113

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Despite recent advances in our understanding of the significance of the protein glycosylation, the throughput of protein glycosylation analysis is still too low to be applied to the exhaustive glycoproteomic analysis. Aiming to elucidate the N-glycosylation of murine epidermis and dermis glycoproteins, here we used a novel approach for focused proteomics. A gross N-glycan profiling (glycomics) of epidermis and dermis was first elucidated both qualitatively and quantitatively upon N-glycan derivatization with novel, stable isotope-coded derivatization reagents followed by MALDI-TOF(/TOF) analysis. This analysis revealed distinct features of the N-glycosylation profile of epidermis and dermis for the first time. A high abundance of high mannose type oligosaccharides was found to be characteristic of murine epidermis glycoproteins. Based on this observation, we performed high mannose type glycoform-focused proteomics by direct tryptic digestion of protein mixtures and affinity enrichment. We The rapid progress in the sequence analysis of genomes of a variety of living organisms is accelerating the investigation of various related proteins involved in biological processes and disorders. Carbohydrate modifications can profoundly affect protein function. Their importance in disease is evident from a growing number of embryonic lethal phenotypes seen in knock-out mice with defects in glycoconjugate assembly or processing (1), and hence a large scale protein glycosylation analysis has become important.The accurate identification of protein glycosylation is challenging because of the complex structures, labile nature, and microheterogeneity of glycoproteins. The presence of nonglycopeptides in a sample also limits the sensitivity for analysis of glycopeptides on mass spectrometry due to ion suppression. Although several new techniques enabling the large scale identification of glycoproteins have recently been developed (2-4), they cannot provide information about oligosaccharide moieties because the analysis is performed on peptides of which such moieties are enzymatically removed prior to the analysis. It is also well known that glycosylation is cell type-specific, so a single glycoprotein can have a different spectrum of glycan structures when expressed in different cells. Recent progress in mass spectrometry (e.g. electron capture-induced dissociation using Fourier transform mass spectrometry (5, 6) and MALDI-LIFT-TOF/TOF (7)) has demonstrated the ability to provide information both on peptide sequence and glycan structure for the analysis of glycopeptides. However, the throughput of these techniques is not high enough to apply to large scale protein glycosylation analyses. Therefore, unveiling the significance of protein glycosylation in an efficient manner requires further thought. One solution is to develop a focused approach based on function and information content.In this study, we describe a glycomic approach to rationalize the focusing process using murine dermis and epidermis as models. A gross N-glycan profi...

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“…The presence of the 52-kDa form was shown in the spinous layer and activation occurred in the granular layer (48 kDa and 33 kDa form). These two active forms were present in the stratum corneum, where they played a role in epidermal desquamation (Horikoshi et al, 1998;Igarashi et al, 2004). Although, the role of CD in epidermal differentiation has been defined, the presence of pCD at different stages of differentiation is still unclear.…”

Section: Introductionmentioning

confidence: 99%

Procathepsin D secreted by HaCaT keratinocyte cells – A novel regulator of keratinocyte growth

Vashishta¹,

Ohri²,

Větvičková³

et al. 2007

European Journal of Cell Biology

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Procathepsin D (pCD), the precursor form of lysosomal aspartic protease, is overexpressed and secreted by various carcinomas. The fact that secreted pCD plays an essential role in progression of cancer has been established. In this study, we describe substantial secretion of pCD by the human keratinocyte cell line HaCaT, under serum-free conditions. Moreover, exogenous addition of purified pCD enhanced the proliferation of HaCaT cells. The proliferative effect of pCD was inhibited by a monoclonal antibody against the activation peptide (AP) of pCD. Treatment of HaCaT cells with pCD or AP led to the secretion of a set of cytokines that might promote the growth of cells in a paracrine manner. The role of secreted pCD and its mechanism of action were studied in a scratch wound model and the presence of pCD and AP enhanced regeneration, while this effect was reversed by the addition of anti-AP antibody. Expression and secretion of pCD was upregulated in HaCaT cells exposed to various stress conditions. Taken together, our results strongly suggest that the secretion of pCD is not only linked to cancer cells but also plays a role in normal physiological conditions like wound healing and tissue remodeling.

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Cathepsin D, but not cathepsin E, degrades desmosomes during epidermal desquamation

Abstract: We conclude that cathepsin D, and not cathepsin E, causes desquamation by degrading desmosomes.

Cited by 54 publications

References 19 publications

Premature Terminal Differentiation and a Reduction in Specific Proteases Associated with Loss of ABCA12 in Harlequin Ichthyosis

Premature Terminal Differentiation and a Reduction in Specific Proteases Associated with Loss of ABCA12 in Harlequin Ichthyosis

High Throughput Quantitative Glycomics and Glycoform-focused Proteomics of Murine Dermis and Epidermis

Procathepsin D secreted by HaCaT keratinocyte cells – A novel regulator of keratinocyte growth

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