Dataset Information

HSP47 Increases the Expression of Type I Collagen in Fibroblasts through IRE1α Activation, XBP1 Splicing, and Nuclear Translocation of β-Catenin.

ABSTRACT: Heat shock protein 47 (HSP47), also known as SERPINH1, functions as a collagen-specific molecular chaperone protein essential for the formation and stabilization of the collagen triple helix. Here, we delved into the regulatory pathways governed by HSP47, shedding light on collagen homeostasis. Our investigation revealed a significant reduction in HSP47 mRNA levels in the skin tissue of older mice as compared to their younger counterparts. The augmented expression of HSP47 employing lentivirus infection in fibroblasts resulted in an increased secretion of type I collagen. Intriguingly, the elevated expression of HSP47 in fibroblasts correlated with increased protein and mRNA levels of type I collagen. The exposure of fibroblasts to IRE1α RNase inhibitors resulted in the reduced manifestation of HSP47-induced type I collagen secretion and expression. Notably, HSP47-overexpressing fibroblasts exhibited increased XBP1 mRNA splicing. The overexpression of HSP47 or spliced XBP1 facilitated the nuclear translocation of β-catenin and transactivated a reporter harboring TCF binding sites on the promoter. Furthermore, the overexpression of HSP47 or spliced XBP1 or the augmentation of nuclear β-catenin through Wnt3a induced the expression of type I collagen. Our findings substantiate that HSP47 enhances type I collagen expression and secretion in fibroblasts by orchestrating a mechanism that involves an increase in nuclear β-catenin through IRE1α activation and XBP1 splicing. This study therefore presents potential avenues for an anti-skin-aging strategy targeting HSP47-mediated processes.

SUBMITTER: Ham SY

PROVIDER: S-EPMC10969015 | biostudies-literature | 2024 Mar

REPOSITORIES: biostudies-literature

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HSP47 Increases the Expression of Type I Collagen in Fibroblasts through IRE1α Activation, XBP1 Splicing, and Nuclear Translocation of β-Catenin.

Ham So Young SY Pyo Min Ju MJ Kang Moonkyung M Kim Yeon-Soo YS Lee Dong Hun DH Chung Jin Ho JH Lee Seung-Taek ST

Cells 20240317 6

Heat shock protein 47 (HSP47), also known as <i>SERPINH1</i>, functions as a collagen-specific molecular chaperone protein essential for the formation and stabilization of the collagen triple helix. Here, we delved into the regulatory pathways governed by HSP47, shedding light on collagen homeostasis. Our investigation revealed a significant reduction in <i>HSP47</i> mRNA levels in the skin tissue of older mice as compared to their younger counterparts. The augmented expression of HSP47 employin ...[more]

PMID: 38534372

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Project description:Fibrosis, characterised by excessive extracellular matrix deposition, contributes to both organ failure and significant mortality worldwide. Whereas fibroblasts are activated into myofibroblasts, marked by phenotypic factors such as α-smooth muscle actin (α-SMA), periostin, fibroblast activation protein (FAP) and heat shock protein 47 (HSP47), the cellular processes of trans-differentiation for fibrosis development remain poorly understood. Herein, we hypothesised that the molecular signalling of geranylgeranyl pyrophosphate (GGPP), a crucial biochemical molecule for protein prenylation, is essential in the regulation of profibrotic mechanisms for fibroblast-to-myofibroblast activation. To test this hypothesis, we demonstrated pharmacological inhibition of geranylgeranyl pyrophosphate synthase (GGPS1) significantly decreased TGF-β1-dependent myofibroblast differentiation assessed by reduced α-SMA, periostin, FAP and HSP47 expression. Exogenous GGPP in the presence of GGPS1 inhibition restored TGF-β1-induced differentiation, supporting posttranslational requirements of GGPP modification during myofibroblast differentiation. Selective inhibition of either geranylgeranyl transferase or farnesyl transferase significantly impacted TGF-β1-induced myofibroblast α-SMA and HSP47 expression. The importance of protein prenylation as a key regulator of myofibroblast differentiation was remarkably revealed by an unexpected decrease in HSP47 expression. In contrast, direct HSP47 inhibition not only suppressed TGF-β1-induced α-SMA expression but surprisingly could not be rescued using exogenous GGPP. A selective role for the ER-resident chaperone HSP47 expression downstream of GGPP was suggested when the effects of GGPS1 inhibition on periostin expression were counteracted by GGPP and geranylgeranyl transferase inhibition. Taken together, our findings underscore for the first time the functional role of cholesterol synthesis-independent GGPP-dependent pathway in fibroblast-to-myofibroblast transition and open new potential therapeutic targets for antifibrosis therapies.

Dataset Information

HSP47 Increases the Expression of Type I Collagen in Fibroblasts through IRE1α Activation, XBP1 Splicing, and Nuclear Translocation of β-Catenin.

Publications

HSP47 Increases the Expression of Type I Collagen in Fibroblasts through IRE1α Activation, XBP1 Splicing, and Nuclear Translocation of β-Catenin.

Similar Datasets

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