Nature communications, 2021-07, Vol.12 (1), p.4404-4404, Article 4404
2021
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- Autor(en) / Beteiligte
- Titel
- TGFβ promotes fibrosis by MYST1-dependent epigenetic regulation of autophagy
- Ist Teil von
- Nature communications, 2021-07, Vol.12 (1), p.4404-4404, Article 4404
- Ort / Verlag
- England: Nature Publishing Group
- Erscheinungsjahr
- 2021
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- Activation of fibroblasts is essential for physiological tissue repair. Uncontrolled activation of fibroblasts, however, may lead to tissue fibrosis with organ dysfunction. Although several pathways capable of promoting fibroblast activation and tissue repair have been identified, their interplay in the context of chronic fibrotic diseases remains incompletely understood. Here, we provide evidence that transforming growth factor-β (TGFβ) activates autophagy by an epigenetic mechanism to amplify its profibrotic effects. TGFβ induces autophagy in fibrotic diseases by SMAD3-dependent downregulation of the H4K16 histone acetyltransferase MYST1, which regulates the expression of core components of the autophagy machinery such as ATG7 and BECLIN1. Activation of autophagy in fibroblasts promotes collagen release and is both, sufficient and required, to induce tissue fibrosis. Forced expression of MYST1 abrogates the stimulatory effects of TGFβ on autophagy and re-establishes the epigenetic control of autophagy in fibrotic conditions. Interference with the aberrant activation of autophagy inhibits TGFβ-induced fibroblast activation and ameliorates experimental dermal and pulmonary fibrosis. These findings link uncontrolled TGFβ signaling to aberrant autophagy and deregulated epigenetics in fibrotic diseases and may contribute to the development of therapeutic interventions in fibrotic diseases.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 2041-1723eISSN: 2041-1723DOI: 10.1038/s41467-021-24601-yTitel-ID: cdi_doaj_primary_oai_doaj_org_article_62b5d5ace81c405bb445c8cf7e9725a7
- Format
- –
- Schlagworte
- Adult, Aged, Animals, Autophagy, Autophagy - genetics, Autophagy-Related Protein 7 - genetics, Autophagy-Related Protein 7 - metabolism, Biopsy, Case-Control Studies, Collagen, Deregulation, Disease Models, Animal, Down-Regulation, Epigenesis, Genetic, Epigenetics, Female, Fibroblasts, Fibrosis, Gene Knockout Techniques, Growth factors, Healthy Volunteers, Histone acetyltransferase, Histone Acetyltransferases - metabolism, Humans, Lung diseases, Male, Mice, Mice, Transgenic, Middle Aged, NIH 3T3 Cells, Phagocytosis, Primary Cell Culture, Receptors, Transforming Growth Factor beta, Repair, Scleroderma, Systemic - pathology, Signal Transduction - genetics, Skin - cytology, Skin - pathology, Smad3 protein, Smad3 Protein - metabolism, Systemic sclerosis, Therapeutic applications, Tissues, Transforming Growth Factor beta - metabolism, Transforming growth factor-b, Young Adult