Dysregulation of STS in keratinocytes promotes calcium signaling and hyperkeratinization: Insights into the mechanisms underlying X-linked ichthyosis DOI Creative Commons

Tae-Uk Kwon,

Yeo‐Jung Kwon,

Hyemin Park

et al.

Research Square (Research Square), Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 12, 2024

Abstract Steroid sulfatase (STS) is a key enzyme for the desulfation of steroid sulfates, converting them into their biologically active forms. Notably, X-linked ichthyosis (XLI), genetic disorder characterized by hyperkeratinization, arises as direct result STS deficiency. Keratinocyte differentiation essential proper keratinization. In this study, gene ontology analysis from STS-deficient mice revealed enhanced and upregulation calcium-related signaling. Calcium plays role in regulating keratinocyte differentiation, with cells showing marked increase intracellular calcium influx. Additionally, these significantly upregulated calcium-sensing receptors (CasR), leading to elevated tyrosine phosphorylation, increased signaling, early markers, including keratin 1 10, seen HaCaT mouse primary keratinocytes. Furthermore, inhibitors expression E-cadherin late markers such involucrin loricrin. Due sensitivity, treated exhibited significant reduced sensitivity chelation. Collectively, our findings demonstrate that inhibition its activity enhance responsiveness, induce CasR expression, amplify thereby promoting differentiation. These offer valuable insights mechanisms underlying deficiency-induced hyperkeratinization.

Language: Английский

Steroid sulfatase suppresses keratinization by inducing proteasomal degradation of E-cadherin via Hakai regulation DOI Creative Commons

Tae-Uk Kwon,

Yeo‐Jung Kwon,

Hyemin Park

et al.

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research, Journal Year: 2025, Volume and Issue: 1872(3), P. 119898 - 119898

Published: Jan. 6, 2025

X-linked ichthyosis (XLI) is a genetic disorder characterized by steroid sulfatase (STS) deficiency inducing excessive cholesterol sulfate accumulation and keratinization. Our study utilizes STS knockout mice to reproduce the hyperkeratinization typical of XLI, providing valuable model for investigating underlying mechanisms. From experiment STS-deficient keratinocytes using CRISPR/Cas9 system, we observed upregulation E-cadherin, which associated with keratinocyte differentiation stratification. This was accompanied elevated levels keratinization markers, including involucrin loricrin. We also found an increased expression SULT2B1, converts sulfate, further accelerating accumulation. As result, lead decreased Hakai, ubiquitin E3 ligase E-cadherin. With reduced endocytosis ubiquitin-mediated degradation E-cadherin are inhibited, resulting in its stabilization. stabilization loricrin, suppressed when N-terminal extracellular domain responsible cell-cell adhesion, genetically modified. propose that inhibition modification domain, treatment miR-6766 targeting significantly reduce suggesting potential therapeutic approach. suggest regulated underscoring central role pathogenesis XLI.

Language: Английский

Citations

0
Dysregulation of STS in keratinocytes promotes calcium signaling and differentiation DOI Creative Commons

Tae-Uk Kwon,

Yeo‐Jung Kwon,

Hyemin Park

et al.

Scientific Reports, Journal Year: 2025, Volume and Issue: 15(1)

Published: March 21, 2025

Steroid sulfatase (STS) is a key enzyme for the desulfation of steroid sulfates, converting them into their biologically active forms. Notably, X-linked ichthyosis (XLI), genetic disorder characterized by hyperkeratinization, arises as direct result STS deficiency. Keratinocyte differentiation essential proper keratinization. In this study, gene ontology analysis from STS-deficient mice revealed enhanced and upregulation calcium-related signaling. Calcium plays role in regulating keratinocyte differentiation, with cells showing marked increase intracellular calcium influx. Additionally, these significantly upregulated calcium-sensing receptors (CasR), leading to elevated tyrosine phosphorylation, increased signaling, early markers, including keratin 1 10, seen HaCaT mouse primary keratinocytes. Furthermore, inhibitors expression E-cadherin terminal markers such involucrin loricrin. Due sensitivity, treated exhibited significant reduced sensitivity chelation. Collectively, our findings demonstrate that inhibition its activity enhance responsiveness, induce CasR expression, amplify thereby promoting differentiation. These offer valuable insights mechanisms underlying deficiency-induced hyperkeratinization.

Language: Английский

Citations

0
Cardiac arrhythmia in individuals with steroid sulfatase deficiency (X-linked ichthyosis): candidate anatomical and biochemical pathways DOI Creative Commons
Georgina H. Wren, William Davies

Essays in Biochemistry, Journal Year: 2024, Volume and Issue: unknown

Published: April 4, 2024

Abstract Circulating steroids, including sex hormones, can affect cardiac development and function. In mammals, steroid sulfatase (STS) is the enzyme solely responsible for cleaving sulfate groups from various molecules, thereby altering their activity water solubility. Recent studies have indicated that Xp22.31 genetic deletions encompassing STS (associated with rare dermatological condition X-linked ichthyosis), common variants within gene, are associated a markedly elevated risk of arrhythmias, notably atrial fibrillation/flutter. Here, we consider emerging basic science clinical findings which implicate structural heart abnormalities (notably septal defects) as mediator this heightened risk, propose candidate cellular biochemical mechanisms. Finally, how biological link between structure/function might be investigated further implications work in area.

Language: Английский

Citations

2
Revisiting X‐linked congenital ichthyosis DOI

Baishun Zhou,

Cancan Liang,

Peiyao Li

et al.

International Journal of Dermatology, Journal Year: 2024, Volume and Issue: unknown

Published: July 31, 2024

Abstract X‐linked recessive ichthyosis (XLI) is a hereditary skin disease characterized by generalized dryness and scaling of the skin, with frequent extracutaneous manifestations. It second most common type ichthyosis, prevalence 1/6,000 to 1/2,000 in males without any racial or geographical differences. The causative gene for XLI steroid sulfatase ( STS ), located on Xp22.3. deficiency causes an abnormal cholesterol sulfate (CS) accumulation stratum corneum (SC). Excess CS induces epidermal permeability barrier dysfunction abnormalities. This review summarizes XLI's genetic, clinical, pathological features, pathogenesis, diagnosis differential diagnoses, therapeutic perspectives. Further understanding role pathogenic variants may contribute more accurate efficient clinical provide novel strategies its treatment prenatal diagnosis.

Language: Английский

Citations

1
Comprehensive Molecular Analysis of Disease-Related Genes as First-Tier Test for Early Diagnosis, Classification, and Management of Patients Affected by Nonsyndromic Ichthyosis DOI Creative Commons
Tiziana Fioretti, Fabrizio Martora,

Ilaria Maggio

et al.

Biomedicines, Journal Year: 2024, Volume and Issue: 12(5), P. 1112 - 1112

Published: May 17, 2024

Inherited ichthyoses are a group of clinically and genetically heterogeneous rare disorders skin keratinization with overlapping phenotypes. The clinical picture family history crucial to formulating the diagnostic hypothesis, but only identification genetic defect allows correct classification. In attempt molecularly classify 17 unrelated Italian patients referred congenital nonsyndromic ichthyosis, we performed massively parallel sequencing over 50 ichthyosis-related genes. Genetic data 300 unaffected subjects were also analyzed evaluate frequencies putative disease-causing alleles in our population. For all patients, identified molecular cause disease. Eight affected by autosomal recessive ichthyosis associated ALOX12B, NIPAL4, TGM1 mutations. Three had biallelic loss-of-function variants FLG, whereas 6/11 males X-linked ichthyosis. Among 24 different identified, 8 carried novel variants, including synonymous variant that resulted splicing defect. Moreover, generated priority list genes showed significant number conclusion, comprehensive analysis an effective first-tier test for early classification patients. It expands genetic, mutational, phenotypic spectra inherited provides new insight into current understanding etiologies epidemiology this disorders.

Language: Английский

Citations

0
Unveiling ferroptosis: a new frontier in skin disease research DOI Creative Commons
Ke Wang,

Yumeng Lin,

Dan Zhou

et al.

Frontiers in Immunology, Journal Year: 2024, Volume and Issue: 15

Published: Oct. 4, 2024

Ferroptosis, a form of regulated cell death distinct from apoptosis, necrosis, and autophagy, is increasingly recognized for its role in skin disease pathology. Characterized by iron accumulation lipid peroxidation, ferroptosis has been implicated the progression various conditions, including psoriasis, photosensitive dermatitis, melanoma. This review provides an in-depth analysis molecular mechanisms underlying compares cellular effects with other forms context health disease. We systematically examine five specific diseases, ichthyosis, polymorphous light eruption (PMLE), vitiligo, melanoma, detailing influence on pathogenesis progression. Moreover, we explore current clinical landscape ferroptosis-targeted therapies, discussing their potential managing treating diseases. Our aim to shed therapeutic modulating research practice.

Language: Английский

Citations

0
Dysregulation of STS in keratinocytes promotes calcium signaling and hyperkeratinization: Insights into the mechanisms underlying X-linked ichthyosis DOI Creative Commons

Tae-Uk Kwon,

Yeo‐Jung Kwon,

Hyemin Park

et al.

Research Square (Research Square), Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 12, 2024

Abstract Steroid sulfatase (STS) is a key enzyme for the desulfation of steroid sulfates, converting them into their biologically active forms. Notably, X-linked ichthyosis (XLI), genetic disorder characterized by hyperkeratinization, arises as direct result STS deficiency. Keratinocyte differentiation essential proper keratinization. In this study, gene ontology analysis from STS-deficient mice revealed enhanced and upregulation calcium-related signaling. Calcium plays role in regulating keratinocyte differentiation, with cells showing marked increase intracellular calcium influx. Additionally, these significantly upregulated calcium-sensing receptors (CasR), leading to elevated tyrosine phosphorylation, increased signaling, early markers, including keratin 1 10, seen HaCaT mouse primary keratinocytes. Furthermore, inhibitors expression E-cadherin late markers such involucrin loricrin. Due sensitivity, treated exhibited significant reduced sensitivity chelation. Collectively, our findings demonstrate that inhibition its activity enhance responsiveness, induce CasR expression, amplify thereby promoting differentiation. These offer valuable insights mechanisms underlying deficiency-induced hyperkeratinization.

Language: Английский

Citations

0