Year: 2021
Type: article
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.
Source: Nature Communications
Authors: Ariella Zehender, Yi-Nan Li, Neng-Yu Lin, Adrian Stefanica, Julian Nüchel, Chih-Wei Chen, Hsiao-Han Hsu, Honglin Zhu, Xiao Ding, Jingang Huang, Lichong Shen, Andrea-Hermina Györfi, Alina Soare, Simon Rauber, Christina Bergmann, Andreas Ramming, Markus Plomann, Beate Eckes, Georg Schett, Jörg H. W. Distler
Institutions: Friedrich-Alexander-Universität Erlangen-Nürnberg, Universitätsklinikum Erlangen, National Taiwan University, University of Cologne, Central South University, Xiangya Hospital Central South University, Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases
Language: English
Topic: TGF-β signaling in diseases
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $3,721
Awards: G1037940132, G1741633616, G286874467, G3778124041, G378208582, G4045315607, G4412743425, G4473728061, G51866882, G5235087602, G5276858517, G5755764578, G5826877023, G5949669494, SFB 829: Molekulare Grundlagen der Regulation der Homöostase der Haut, TRR 221: Steuerung der TransplantatgegenWirt und TransplantatgegenLeukämieImmunreaktionen nach allogener Stammzelltransplantation, Matrix vermittelte Fibroblastenaktivierung in rheumatoider Arthritis, G684193463, G6871902449, G7578079922, G8475804783
OpenAlex ID: W3186765322