TGFβ promotes fibrosis by MYST1-dependent epigenetic regulation of autophagy

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 and Jörg H. W. Distler ()
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Ariella Zehender: Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and University Hospital Erlangen
Yi-Nan Li: Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and University Hospital Erlangen
Neng-Yu Lin: Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and University Hospital Erlangen
Adrian Stefanica: Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and University Hospital Erlangen
Julian Nüchel: University of Cologne, Faculty of Medicine
Chih-Wei Chen: Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and University Hospital Erlangen
Hsiao-Han Hsu: National Taiwan University
Honglin Zhu: Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and University Hospital Erlangen
Xiao Ding: Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and University Hospital Erlangen
Jingang Huang: Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and University Hospital Erlangen
Lichong Shen: Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and University Hospital Erlangen
Andrea-Hermina Györfi: Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and University Hospital Erlangen
Alina Soare: Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and University Hospital Erlangen
Simon Rauber: Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and University Hospital Erlangen
Christina Bergmann: Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and University Hospital Erlangen
Andreas Ramming: Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and University Hospital Erlangen
Markus Plomann: University of Cologne, Faculty of Medicine
Beate Eckes: University of Cologne, Faculty of Medicine
Georg Schett: Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and University Hospital Erlangen
Jörg H. W. Distler: Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and University Hospital Erlangen

Nature Communications, 2021, vol. 12, issue 1, 1-19

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-24601-y

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