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Ubiquitin Proteomics Analysis of Systemic Sclerosis Lung Fibroblasts with or without KLHL42 knockdown

ABSTRACT: Systemic scleroderma (SSc) is an autoimmune disease which results in fibrotic production in the lung. Resultant SSC-pulmonary fibrosis is the main cause of mortality among SSc patients. From high throughput RNAi screening, we uncovered the ubiquitin E3 ligase KLHL42 as a potential pro-fibrotic mediator of TGFb-dependent fibrotic signaling in primary SSc lung fibroblasts. In this analysis, we sought to uncover putative substrates for KLHL42 by comparing SSc lung fibroblasts with control or KLHL42 siRNA prior to TGFb-treatment, lysis, and TUBE precipitation. The resultant pull-down was analyzed with LC-MS/MS.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (ncbitaxon:9606)

SUBMITTER: Bill Chen

PROVIDER: MSV000084800 | MassIVE | Tue Jan 14 05:30:00 GMT 2020

REPOSITORIES: MassIVE

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Kelch-like protein 42 is a profibrotic ubiquitin E3 ligase involved in systemic sclerosis.

Lear Travis B TB Lockwood Karina C KC Larsen Mads M Tuncer Ferhan F Kennerdell Jason R JR Morse Christina C Valenzi Eleanor E Tabib Tracy T Jurczak Michael J MJ Kass Daniel J DJ Evankovich John W JW Finkel Toren T Lafyatis Robert R Liu Yuan Y Chen Bill B BB

The Journal of biological chemistry 20200217 13

Systemic scleroderma (SSc) is an autoimmune disease that affects over 2.5 million people globally. SSc results in dysfunctional connective tissues with excessive profibrotic signaling, affecting skin, cardiovascular, and particularly lung tissue. Over three-quarters of individuals with SSc develop pulmonary fibrosis within 5 years, the main cause of SSc mortality. No approved medicines to manage lung SSc currently exist. Recent research suggests that profibrotic signaling by transforming growth ...[more]

PMID: 32071084

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PTP4A1 phosphatase is overexpressed in systemic sclerosis fibroblasts and promotes TGFb signaling

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Epigenetic activation and memory at a TGFB2 enhancer in systemic sclerosis

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2021-05-20 | GSE138669 | GEO

Expression of miRNA from lung tissue from Systemic Sclerosis patients with interstitial lung disease (SSc-ILD) and healthy controls.

Project description:Objective: MicroRNAs (miRNAs) control key elements of mRNA stability and likely contribute to the dysregulated lung gene expression observed in systemic sclerosis associated interstitial lung disease (SSc-ILD). We analyzed the miRNA gene expression of tissue and cells from SSc-ILD patients. A chronic lung fibrotic murine model was used. Methods: RNA was isolated from lung tissue of 12 SSc-ILD patients and 5 control lungs. High-resolution computed tomography (HRCT) was performed at baseline and 2-3 years after treatment. Lung fibroblasts and PBMCs were isolated from healthy controls and SSc-ILD patients. miRNA and mRNA were analyzed by microarray, quantitative polymerase chain reaction, and/or Nanostring; pathway analysis was performed by DIANA-miRPath v2.0 software. Wild-type and miR-155 deficient (miR-155ko) mice were exposed to bleomycin. Results: Lung miRNA microarray data distinguished patients with SSc-ILD from healthy controls with 185 miRNA differentially expressed (q<0.25). DIANA-miRPath revealed 57 KEGGs pathways related to the most dysregulated miRNAs. miR-155 and miR-143 were strongly correlated with progression of the HRCT score. Lung fibroblasts showed only mild expression of miR-155/miR-21 after several stimuli. miR-155 PBMC expression strongly correlated with lung function tests in SSc-ILD. miR-155ko mice developed milder lung fibrosis, survived longer, and showed a weaker lung induction of several genes after bleomycin exposure compared to wild-type mice. Conclusions: miRNAs are dysregulated in lungs and PBMCs of SSc-ILD patients. Based on mRNA-miRNA interaction analysis and pathway tools, miRNAs may play a role in the progression of the disease. Our findings suggest that targeting miR-155 might provide a novel therapeutic strategy for SSc-ILD. Lung biopsies taken from open lung biopsy from SSc-ILD patients (n=15 samples) and from cancer free control patients (n=5) during ressection of the lung tumor.

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Expression of mRNA from lung tissue from Systemic Sclerosis patients with interstitial lung disease (SSc-ILD) and healthy controls (HC)

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Impaired TFAM expression promotes mitochondrial damage to drive fibroblast activation and fibrosis in systemic sclerosis

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2021-12-21 | GSE184356 | GEO

Gene expression in limited cutaneous systemic sclerosis skin

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2017-01-01 | GSE76806 | GEO

Expression of miRNA from lung tissue from Systemic Sclerosis patients with interstitial lung disease (SSc-ILD) and healthy controls.

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Expression of mRNA from lung tissue from Systemic Sclerosis patients with interstitial lung disease (SSc-ILD) and healthy controls (HC)

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