TGFβ promotes fibrosis by MYST1-dependent epigenetic regulation of autophagy
Journal
Nature communications
Journal Volume
12
Journal Issue
1
Date Issued
2021
Author(s)
Zehender, Ariella
Li, Yi-Nan
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
Abstract
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.
Subjects
GROWTH-FACTOR-BETA; PULMONARY-FIBROSIS; FIBROBLAST ACTIVATION; UNCONVENTIONAL SECRETION; HISTONE DEACETYLASE; SYSTEMIC-SCLEROSIS; LIVER FIBROSIS; INHIBITION; DISEASE; CELLS
SDGs
Other Subjects
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
Publisher
NATURE RESEARCH
Type
journal article