Cholesterol Sulfate Inhibits Proteases that are Involved in Desquamation of Stratum Corneum

Sato, Junko; Denda, Mitsuhiro; Nakanishi, Jotaro; Nomura, Junko; Koyama, Junichi

doi:10.1046/j.1523-1747.1998.00244.x

Cited by 104 publications

(77 citation statements)

References 17 publications

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“…Cholesterol sulfate has been noted to inhibit the pancreatic serine proteases trypsin and chymotrypsin (103,104) as well as a yeast pronase (103); it also inhibits pancreatic elastase (105) and DNase I (106). The physiologic significance of these in vitro findings, however, is not fully appreciated.…”

Section: Enzyme Systemsmentioning

confidence: 99%

Cholesterol sulfate in human physiology: what's it all about?

Strott

Higashi

2003

Journal of Lipid Research

206

184

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Cholesterol sulfate is quantitatively the most important known sterol sulfate in human plasma, where it is present in a concentration that overlaps that of the other abundant circulating steroid sulfate, dehydroepiandrosterone (DHEA) sulfate. Although these sulfolipids have similar production and metabolic clearance rates, they arise from distinct sources and are metabolized by different pathways. While the function of DHEA sulfate remains an enigma, cholesterol sulfate has emerged as an important regulatory molecule. Cholesterol sulfate is a component of cell membranes where it has a stabilizing role, e.g., protecting erythrocytes from osmotic lysis and regulating sperm capacitation. It is present in platelet membranes where it supports platelet adhesion. Cholesterol sulfate can regulate the activity of serine proteases, e.g., those involved in blood clotting, fibrinolysis, and epidermal cell adhesion. As a result of its ability to regulate the activity of selective protein kinase C isoforms and modulate the specificity of phosphatidylinositol 3-kinase, cholesterol sulfate is involved in signal transduction. Cholesterol sulfate functions in keratinocyte differentiation, inducing genes that encode for key components involved in development of the barrier. The accumulating evidence demonstrating a regulatory function for cholesterol sulfate appears solid; the challenge now is to work out the molecular mechanisms whereby this interesting molecule carries out its various roles. -Strott, C. A., and Y. Higashi. Cholesterol sulfate in human physiology: what's it all about? J.

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Section: Enzyme Systemsmentioning

confidence: 99%

Cholesterol sulfate in human physiology: what's it all about?

Strott

Higashi

2003

Journal of Lipid Research

206

184

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“…It was proposed that since CSO 4 has trypsin and chymotrypsin inhibitory properties in vitro, it might thereby affect breakdown of desmosomes, thus causing retention hyperkeratoses and abnormal scaling (18). The strong charge of its sulfate moiety conferring mild detergent properties to CSO 4 was shown to interfere with spontaneous sheet-formation of epidermal lipids in vivo and thus theorized to affect epidermal barrier function by deranging skin lipid layers, repressing cholesterol synthesis, and replacing cholesterol in the lipid sheets (16).…”

Section: Effect Of Slv Content Of Cso 4 On -Hydroxyceramidementioning

confidence: 99%

“…Thus it was theorized that CSO 4 affects epidermal barrier function both by deranging skin lipid layers and by replacing cholesterol in the lipid sheets (16). In another study, it was proposed that since CSO 4 has trypsin and chymotrypsin inhibitory properties in vitro, it might thereby affect breakdown of desmosomes, thus causing retention hyperkeratosis and abnormal scaling (18). Finally, more recently, it was demonstrated that CSO 4 can induce TGase 1 expression in cultured keratinocytes (19), but the connection between excess TGase expression and disease etiology remains unclear.…”

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confidence: 99%

“…Mammalian involucrins evolved by tandem duplications of glutamine and glutamic acid-rich sequences spanning between the evolutionary relatively conserved amino-terminal ("head") and carboxyl-terminal ("tail") domains (42 18 HPLC profiles of tryptic involucrin peptides were compared before (A) and after (B) reaction with TGase 1 bound to SLV containing no CSO 4 . Peaks harboring the 5 Gln residues reactive with SLV-bound TGase 1 are indicated with arrows on panel A.…”

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Cholesterol 3-Sulfate Interferes with Cornified Envelope Assembly by Diverting Transglutaminase 1 Activity from the Formation of Cross-links and Esters to the Hydrolysis of Glutamine

Nemes¹,

Demény²,

Marekov³

et al. 2000

Journal of Biological Chemistry

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The loss of transglutaminase 1 enzyme (TGase 1) activity causes lamellar ichthyosis. Recessive X-linked ichthyosis (XI) results from accumulation of excess cholesterol 3-sulfate (CSO 4 ) in the epidermis but the pathomechanism how elevated epidermal CSO 4 causes ichthyosis is largely unknown. Here we provide evidence that XI is also a consequence of TGase 1 dysfunction. TGase 1 is a key component of barrier formation in keratinocytes: it participates in the cross-linking of cell envelope (CE) structural proteins, and also forms the lipid bound envelope by esterification of long chain -hydroxyceramides onto CE proteins. Using involucrin and an epidermal -hydroxyceramide analog as substrates, kinetic analyses revealed that at membrane concentrations above 4 mol %, CSO 4 caused a marked and dose-dependent inhibitory effect on isopeptide and ester bond formation. Sequencing of tryptic peptides from TGase 1-reacted involucrin showed a large increase in deamidation of substrate glutamines. We hypothesize that supraphysiological levels of CSO 4 in keratinocyte membranes distort the structure of TGase 1 and facilitate the access of water into its active site causing hydrolysis of substrate glutamine residues. Our findings provide further evidence for the pivotal role of the TGase 1 enzyme in CE formation.Assembly of an effective epidermal barrier structure is an essential adaptation to terrestrial life. In mammals the outermost bulwark of this barrier is the cornified layer of the epidermis, composed of flattened corneocytes mortared together by orderly lipid laminae. During terminal differentiation, individual corneocytes acquire a specialized cell peripheral structure termed the cornified cell envelope (CE), 1 which is responsible for maintenance of mechanical and chemical protection and indirectly contributes to water permeability barrier (see Refs. 1 and 2, for reviews). The CE is composed of two parts. The ϳ10 nm thick protein envelope is formed by covalent cross-linking of several structural proteins by sulfhydryl oxidases and transglutaminases (TGases). This highly insoluble protein meshwork is coated by the lipid envelope, a ϳ5 nm thick layer of -hydroxyceramides with uniquely long (C 28 -C 36 ) fatty acyl moieties (3). These are covalently attached by ester bonds through their -hydroxyl group to selected glutamines to envoplakin, periplakin, and involucrin components of the protein envelope (4).Terminal differentiation of keratinocytes is accompanied by vigorous lipid metabolism and synthesis of keratinization-specific lipids in the granular layer. Newly synthesized lipids are temporarily stored in cytoplasmic lamellar bodies, in which they are arranged as stacks of tetralaminar sheets. The lamellar body lipids consist largely of free fatty acids, (glucosyl)ceramides, cholesterol, and its acyl or sulfate esters (3). In the uppermost granular layer the lamellar bodies fuse with the cell membrane, and release their contents which assume broad, multilamellar lipid sheets between corneocytes. This process approxima...

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“…CS is a component of cell membranes where it has a stabilizing role and is abundant in the human body with many physiological characteristics 26 . Although CS is already known to inhibit various human proteases [27][28][29][30] and DNase I…”

Section: Discussionmentioning

confidence: 99%

Cholesterol sulfate as a potential inhibitor of hepatitis C virus NS3 helicase

Furuta

Salam

Akimitsu

et al. 2013

Journal of Enzyme Inhibition and Medicinal Chemistry

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Hepatitis C virus nonstructural protein 3 (NS3) helicase is a promising target for developing new therapeutics. In this study, we identified cholesterol sulfate (CS) as a novel NS3 helicase inhibitor (IC 50 ¼ 1.7 AE 0.2 mM with a Hill coefficient of 3.9) by screening the extracts from marine organisms. The lack of the sulfate group, sterol structure or alkyl side chain of CS diminished the inhibition, suggesting that an anion binding and hydrophobic region in NS3 may be a target site of CS. It was further found that CS partly inhibits NS3-RNA binding activity, but exerted no or less inhibition against ATPase and serine protease activities. Moreover, we demonstrated that CS probably does not bind to RNA. Our findings suggest that CS may inhibit NS3 helicase not by abolishing the other NS3 activities but by inducing conformational changes via interaction with possible allosteric sites of NS3.

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Cholesterol Sulfate Inhibits Proteases that are Involved in Desquamation of Stratum Corneum

Cited by 104 publications

References 17 publications

Cholesterol sulfate in human physiology: what's it all about?

Cholesterol sulfate in human physiology: what's it all about?

Cholesterol 3-Sulfate Interferes with Cornified Envelope Assembly by Diverting Transglutaminase 1 Activity from the Formation of Cross-links and Esters to the Hydrolysis of Glutamine

Cholesterol sulfate as a potential inhibitor of hepatitis C virus NS3 helicase

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