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Differential Roles of Cysteinyl Cathepsins in TGF-? Signaling and Tissue Fibrosis.

ABSTRACT: Transforming growth factor beta (TGF-?) signaling contributes to tissue fibrosis. Here we demonstrate that TGF-? enhances CatS and CatK expression but reduces CatB and CatL expression in mouse kidney tubular epithelial cells (TECs). CatS- and CatK deficiency reduces TEC nuclear membrane importer importin-? expression, Smad-2/3 activation, and extracellular matrix (ECM) production. Yet CatB- and CatL-deficiency displays the opposite observations with reduced nuclear membrane exporter RanBP3 expression. CatS and CatK form immunocomplexes with the importin-? and RanBP3 more effectively than do CatB and CatL. On the plasma membrane, CatS and CatK preferentially form immunocomplexes with and activate TGF-? receptor-2, whereas CatB and CatL form immunocomplexes with and inactivate TGF-? receptor-1. Unilateral ureteral obstruction-induced renal injury tests differential cathepsin activities in TGF-? signaling and tissue fibrosis. CatB- or CatL-deficiency exacerbates fibrosis, whereas CatS- or CatK-deficiency protects kidneys from fibrosis. These cathepsins exert different effects in the TGF-? signaling cascade independent of their proteolytic properties.

SUBMITTER: Zhang X

PROVIDER: S-EPMC6715892 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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Differential Roles of Cysteinyl Cathepsins in TGF-β Signaling and Tissue Fibrosis.

Zhang Xian X Zhou Yi Y Yu Xueqing X Huang Qin Q Fang Wenqian W Li Jie J Bonventre Joseph V JV Sukhova Galina K GK Libby Peter P Shi Guo-Ping GP

iScience 20190809

Transforming growth factor beta (TGF-β) signaling contributes to tissue fibrosis. Here we demonstrate that TGF-β enhances CatS and CatK expression but reduces CatB and CatL expression in mouse kidney tubular epithelial cells (TECs). CatS- and CatK deficiency reduces TEC nuclear membrane importer importin-β expression, Smad-2/3 activation, and extracellular matrix (ECM) production. Yet CatB- and CatL-deficiency displays the opposite observations with reduced nuclear membrane exporter RanBP3 expre ...[more]

PMID: 31446224

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Project description:End stage liver disease due to Hepatitis C Virus (HCV) infection is a major health concern worldwide. Liver fibrosis following chronic HCV infection plays a pivotal role in loss of liver function and end stage liver disease. However the dynamics and molecular events that lead to fibrosis in HCV infection are poorly defined. Therefore, we determined the influence of HCV infection in altering the miRNA expression levels which can modulate immune responses to HCV leading to fibrosis. Analysis of the miRNA expression profiles of HCV infected liver biopsies revealed that 45 miRNAs were differentially expressed in the HCV infected liver when compared to normal livers. In silico target prediction of these differentially expressed miRNAs indicated that their targets include chemokine/cytokine signaling, cell cycle genes and extracellular matrix protein gene expression. Gene expression profiling using whole genome microarray demonstrated that 1320 genes were differentially expressed in chronic HCV liver when compared to normal. These genes could be functionally grouped into those involved in cell cycle regulation, cytokines and chemokines expression, cell adhesion, intracellular signaling and enzymes. Further pathway analysis using GeneGo software identified cell adhesion, cytoskeleton remodeling, cytokine signaling and metabolic pathways as the major pathways activated in chronic HCV. Combinatorial target prediction analysis of miRNA expression along with gene expression analysis indicated that differentially expressed microRNAs in HCV significantly impact transforming growth factor beta (TGF-?) signaling pathway, cell adhesion (integrin expression), chemokine signaling, Notch signaling and cell-cycle( Cyclin D,K) regulation. Overall these results demonstrate that chronic HCV infection induces specific miRNA signatures that will modulate genes involved in the cytoskeletal remodeling and cytokine signaling that can promote the development of fibrosis following HCV infection. Liver biopsies from chronic HCV patients and control liver biopsies from normal subjects (donor liver prior to transplantation) were used to analyze the miRNA and gene expression profile. Patients with HBV and/or HIV were excluded from the study. This Series represents the mRNA gene expression profiling data only.

Dataset Information

Differential Roles of Cysteinyl Cathepsins in TGF-? Signaling and Tissue Fibrosis.

Publications

Differential Roles of Cysteinyl Cathepsins in TGF-β Signaling and Tissue Fibrosis.

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