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TGFβ promotes fibrosis by MYST1-dependent epigenetic regulation of autophagy

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  • Ariella Zehender

    (Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and University Hospital Erlangen
    Friedrich Alexander University Erlangen-Nuremberg and Universitaetsklinikum Erlangen)

  • Yi-Nan Li

    (Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and University Hospital Erlangen
    Friedrich Alexander University Erlangen-Nuremberg and Universitaetsklinikum Erlangen)

  • Neng-Yu Lin

    (Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and University Hospital Erlangen
    Friedrich Alexander University Erlangen-Nuremberg and Universitaetsklinikum Erlangen
    National Taiwan University)

  • Adrian Stefanica

    (Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and University Hospital Erlangen
    Friedrich Alexander University Erlangen-Nuremberg and Universitaetsklinikum Erlangen)

  • Julian Nüchel

    (University of Cologne, Faculty of Medicine)

  • Chih-Wei Chen

    (Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and University Hospital Erlangen
    Friedrich Alexander University Erlangen-Nuremberg and Universitaetsklinikum Erlangen)

  • Hsiao-Han Hsu

    (National Taiwan University)

  • Honglin Zhu

    (Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and University Hospital Erlangen
    Friedrich Alexander University Erlangen-Nuremberg and Universitaetsklinikum Erlangen
    Central South University)

  • Xiao Ding

    (Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and University Hospital Erlangen
    Friedrich Alexander University Erlangen-Nuremberg and Universitaetsklinikum Erlangen)

  • Jingang Huang

    (Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and University Hospital Erlangen
    Friedrich Alexander University Erlangen-Nuremberg and Universitaetsklinikum Erlangen)

  • Lichong Shen

    (Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and University Hospital Erlangen
    Friedrich Alexander University Erlangen-Nuremberg and Universitaetsklinikum Erlangen)

  • Andrea-Hermina Györfi

    (Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and University Hospital Erlangen
    Friedrich Alexander University Erlangen-Nuremberg and Universitaetsklinikum Erlangen)

  • Alina Soare

    (Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and University Hospital Erlangen
    Friedrich Alexander University Erlangen-Nuremberg and Universitaetsklinikum Erlangen)

  • Simon Rauber

    (Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and University Hospital Erlangen
    Friedrich Alexander University Erlangen-Nuremberg and Universitaetsklinikum Erlangen)

  • Christina Bergmann

    (Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and University Hospital Erlangen
    Friedrich Alexander University Erlangen-Nuremberg and Universitaetsklinikum Erlangen)

  • Andreas Ramming

    (Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and University Hospital Erlangen
    Friedrich Alexander University Erlangen-Nuremberg and Universitaetsklinikum Erlangen)

  • Markus Plomann

    (University of Cologne, Faculty of Medicine)

  • Beate Eckes

    (University of Cologne, Faculty of Medicine
    Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD))

  • Georg Schett

    (Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and University Hospital Erlangen
    Friedrich Alexander University Erlangen-Nuremberg and Universitaetsklinikum Erlangen)

  • Jörg H. W. Distler

    (Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and University Hospital Erlangen
    Friedrich Alexander University Erlangen-Nuremberg and Universitaetsklinikum Erlangen)

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.

Suggested Citation

  • 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 S, 2021. "TGFβ promotes fibrosis by MYST1-dependent epigenetic regulation of autophagy," Nature Communications, Nature, vol. 12(1), pages 1-19, December.
  • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-24601-y
    DOI: 10.1038/s41467-021-24601-y
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    Cited by:

    1. Bing Yang & Liqing Lu & Ting Xiong & Wei Fan & Jiaohong Wang & Lucía Barbier-Torres & Jyoti Chhimwal & Sonal Sinha & Takashi Tsuchiya & Nirmala Mavila & Maria Lauda Tomasi & DuoYao Cao & Jing Zhang & , 2024. "The role of forkhead box M1-methionine adenosyltransferase 2 A/2B axis in liver inflammation and fibrosis," Nature Communications, Nature, vol. 15(1), pages 1-20, December.

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