The American journal of pathology, 2017-04, Vol.187 (4), p.781-797
2017
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- Autor(en) / Beteiligte
- Titel
- Cathepsin H-Mediated Degradation of HDAC4 for Matrix Metalloproteinase Expression in Hepatic Stellate Cells: Implications of Epigenetic Suppression of Matrix Metalloproteinases in Fibrosis through Stabilization of Class IIa Histone Deacetylases
- Ist Teil von
- The American journal of pathology, 2017-04, Vol.187 (4), p.781-797
- Ort / Verlag
- United States: American Society for Investigative Pathology
- Erscheinungsjahr
- 2017
- Quelle
- Access via ScienceDirect (Elsevier)
- Beschreibungen/Notizen
- In three-dimensional extracellular matrix, mesenchymal cells including hepatic stellate cells (HSCs) gain the ability to express matrix metalloproteinases (MMPs) on injury signals. In contrast, in myofibroblastic HSCs in fibrotic liver, many MMP genes are silenced into an epigenetically nonpermissive state. The mechanism by which the three-dimensional extracellular matrix confers the MMP genes into an epigenetically permissive state has not been well characterized. In continuation of previous work, we show here that the up-regulation of MMP genes is mediated through degradation of class IIa histone deacetylases (HDACs) by certain cysteine cathepsins (Cts). In three-dimensional extracellular matrix culture, CtsH, among other cysteine cathepsins, was up-regulated and localized as puncta in the nuclear and cytoplasmic compartments in a complex with HDAC4 for its degradation. Conversely, along with HSC trans-differentiation, CtsH and CtsL were progressively down-regulated, whereas HDAC4 was concurrently stabilized. The inhibition of cysteine cathepsins by specific proteinase inhibitors or chloroquine, which raises cellular pH, restored HDAC4. Recombinant CtsH could break down HDAC4 in the transfected cells and in vitro at acidic pH. In human cirrhotic liver, activated HSCs express high levels of class IIa HDACs but little CtsH. We propose that cysteine cathepsin-mediated degradation of class IIa HDACs plays a key role in the modulation of MMP expression/suppression and HSC functions in tissue injury and fibrosis.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 0002-9440eISSN: 1525-2191DOI: 10.1016/j.ajpath.2016.12.001Titel-ID: cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_5397721
- Format
- –
- Schlagworte
- Animals, Biocatalysis - drug effects, Cathepsin H - metabolism, Cathepsin L - metabolism, Cell Line, Cell Nucleus - drug effects, Cell Nucleus - metabolism, Cell Transdifferentiation - drug effects, Down-Regulation - drug effects, Down-Regulation - genetics, Enzyme Stability - drug effects, Epigenesis, Genetic - drug effects, Extracellular Matrix - drug effects, Extracellular Matrix - metabolism, Hepatic Stellate Cells - metabolism, Histone Deacetylases - metabolism, Humans, Liver Cirrhosis - enzymology, Liver Cirrhosis - genetics, Liver Cirrhosis - metabolism, Liver Cirrhosis - pathology, Male, Matrix Metalloproteinase 13 - genetics, Matrix Metalloproteinase 13 - metabolism, Matrix Metalloproteinase 9 - metabolism, Mice, Myofibroblasts - drug effects, Myofibroblasts - metabolism, Myofibroblasts - pathology, Protein Binding - drug effects, Proteolysis - drug effects, Rats, Wistar, Recombinant Proteins - metabolism, Regular, Repressor Proteins - metabolism, RNA, Messenger - genetics, RNA, Messenger - metabolism, Subcellular Fractions - metabolism, Tumor Necrosis Factor-alpha - pharmacology