TGFβ promotes fibrosis by MYST1-dependent epigenetic regulation of autophagy

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.

Autophagy in Cisplatin Nephrotoxicity during Cancer Therapy

“…We [14] demonstrated that mice with Atg7 knockout in proximal tubules had fewer atrophic tubules, less apoptosis, and less interstitial fibrosis during UUO. These initial findings are supported by follow-up studies [141][142][143], indicating that autophagy in kidney tubules promotes interstitial fibrosis. Mechanistically, autophagy may induce tubular cell death, cell cycle arrest, and senescence, resulting in the production and secretion of pro-fibrotic and pro-inflammatory cytokines to stimulate fibroblasts for fibrosis [14,138].…”

Proteomes of primary skin fibroblasts from healthy individuals reveal altered cell responses across the life span

“…Fibroblasts are quiescent and are exposed to lower oxygen tension and different endogenous factors, but their ability to proliferate and respond to stress may be an important component of skin aging. Many earlier studies used ex vivo primary fibroblasts to identify molecules affecting the progression of diseases, highlighting the value of this cell model (e.g., Katarkar et al., 2020 ; Zehender et al., 2021 ). Future studies in vivo will be needed to complement the collective results gained from cell culture.…”

“…In our proteomic analysis, the levels of MCM proteins were significantly lower with age (Figure 6a), potentially underscoring the importance of this protein family in DNA metabolism in chronological skin aging. Zehender et al, 2021). Future studies in vivo will be needed to complement the collective results gained from cell culture.…”

Cyclin-Dependent Kinase 5 Regulatory Subunit Associated Protein 3: Potential Functions and Implications for Development and Disease

“…Autophagy is a key intracellular degradation process during which eukaryotic cells clear up harmful or unwanted cytoplasmic contents to maintain cellular homeostasis (49)(50)(51). Current research demonstrates that many factors are involved in modulating this process (19,28,(52)(53)(54). Among them, CDK5RAP3 is reported to regulate autophagy in a renal cancer model (28).…”