https://scholars.lib.ntu.edu.tw/handle/123456789/593999
標題: | TGFβ promotes fibrosis by MYST1-dependent epigenetic regulation of autophagy | 作者: | Zehender, Ariella Li, Yi-Nan NENG-YU LIN Stefanica, Adrian Nüchel, Julian Chen, Chih-Wei Hsu, Hsiao-Han Zhu, Honglin Ding, Xiao Huang, Jingang Shen, Lichong Györfi, Andrea-Hermina Soare, Alina Rauber, Simon Bergmann, Christina Ramming, Andreas Plomann, Markus Eckes, Beate Schett, Georg Distler, Jörg H W |
關鍵字: | GROWTH-FACTOR-BETA; PULMONARY-FIBROSIS; FIBROBLAST ACTIVATION; UNCONVENTIONAL SECRETION; HISTONE DEACETYLASE; SYSTEMIC-SCLEROSIS; LIVER FIBROSIS; INHIBITION; DISEASE; CELLS | 公開日期: | 2021 | 出版社: | NATURE RESEARCH | 卷: | 12 | 期: | 1 | 來源出版物: | Nature communications | 摘要: | 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. |
URI: | https://scholars.lib.ntu.edu.tw/handle/123456789/593999 | ISSN: | 2041-1723 | DOI: | 10.1038/s41467-021-24601-y | SDG/關鍵字: | autophagy related protein 7; beclin 1; collagen type 1; histone acetyltransferase; myst1 protein; Smad3 protein; transforming growth factor beta; unclassified drug; Atg7 protein, human; Atg7 protein, mouse; autophagy related protein 7; histone acetyltransferase; KAT8 protein, human; Kat8 protein, mouse; Smad3 protein; SMAD3 protein, human; Smad3 protein, mouse; transforming growth factor beta; transforming growth factor beta receptor; biological development; biostimulation; collagen; detection method; disease; enzyme; enzyme activity; growth; machinery; physiology; protein; adult; animal cell; animal experiment; animal model; animal tissue; Article; autophagy (cellular); cell activation; controlled study; down regulation; embryo; epigenetics; female; gene knockout; gene overexpression; gene repression; histone acetylation; human; human cell; human tissue; lung fibrosis; male; mouse; myofibroblast; nonhuman; pathogenesis; protein expression; skin fibroblast; skin fibrosis; systemic sclerosis; TGF beta signaling; aged; animal; autophagy; biopsy; case control study; cytology; disease model; fibroblast; fibrosis; genetic epigenesis; genetics; metabolism; middle aged; NIH 3T3 cell line; normal human; pathology; primary cell culture; signal transduction; skin; transgenic mouse; young adult; Adult; Aged; Animals; Autophagy; Autophagy-Related Protein 7; Biopsy; Case-Control Studies; Disease Models, Animal; Down-Regulation; Epigenesis, Genetic; Female; Fibroblasts; Fibrosis; Gene Knockout Techniques; Healthy Volunteers; Histone Acetyltransferases; Humans; Male; Mice; Mice, Transgenic; Middle Aged; NIH 3T3 Cells; Primary Cell Culture; Receptors, Transforming Growth Factor beta; Scleroderma, Systemic; Signal Transduction; Skin; Smad3 Protein; Transforming Growth Factor beta; Young Adult |
顯示於: | 解剖學暨細胞生物學科所 |
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