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Published on: February 27, 2016
SIRT3 Blocks Aging-Associated Tissue Fibrosis in Mice by Deacetylating and Activating Glycogen Synthase Kinase 3β
Nagalingam R Sundaresan1, Samik Bindu1, Vinodkumar B Pillai1
1Department of Surgery, Biological Science Division, University of Chicago, Chicago, Illinois, USA.
Abstract:
Tissue fibrosis is a major cause of organ dysfunction during chronic diseases and aging. A critical step in this process is transforming growth factor β1 (TGF-β1)-mediated transformation of fibroblasts into myofibroblasts, cells capable of synthesizing extracellular matrix. Here, we show that SIRT3 controls transformation of fibroblasts into myofibroblasts via suppressing the profibrotic TGF-β1 signaling. We found that Sirt3 knockout (KO) mice with age develop tissue fibrosis of multiple organs, including heart, liver, kidney, and lungs but not whole-body SIRT3-overexpressing mice. SIRT3 deficiency caused induction of TGF-β1 expression and hyperacetylation of glycogen synthase kinase 3β (GSK3β) at residue K15, which negatively regulated GSK3β activity to phosphorylate the substrates Smad3 and β-catenin. Reduced phosphorylation led to stabilization and activation of these transcription factors regulating expression of the profibrotic genes. SIRT3 deacetylated and activated GSK3β and thereby blocked TGF-β1 signaling and tissue fibrosis. These data reveal a new role of SIRT3 to negatively regulate aging-associated tissue fibrosis and discloses a novel phosphorylation-independent mechanism controlling the catalytic activity of GSK3β.
Insights
Sirtuin 3 (SIRT3) protein prevents tissue fibrosis by suppressing transforming growth factor β1 (TGF-β1) signaling. SIRT3 deficiency accelerates age-related fibrosis in multiple organs, highlighting its protective role.
Area of Science:
- Biochemistry
- Cell Biology
- Aging Research
Background:
- Tissue fibrosis, a hallmark of chronic diseases and aging, leads to organ dysfunction.
- Fibrosis involves the transformation of fibroblasts into myofibroblasts, driven by transforming growth factor β1 (TGF-β1) signaling.
- Myofibroblasts synthesize excessive extracellular matrix, contributing to tissue scarring and loss of function.
Purpose of the Study:
- To investigate the role of Sirtuin 3 (SIRT3) in regulating fibroblast to myofibroblast transformation.
- To elucidate the molecular mechanisms by which SIRT3 influences profibrotic signaling pathways.
- To determine the impact of SIRT3 deficiency or overexpression on age-associated tissue fibrosis.
Main Methods:
- Utilized Sirt3 knockout (KO) and SIRT3-overexpressing mouse models.
- Analyzed age-dependent tissue fibrosis in multiple organs (heart, liver, kidney, lungs).
- Investigated the acetylation status and activity of glycogen synthase kinase 3β (GSK3β) and its downstream targets (Smad3, β-catenin) in response to SIRT3 modulation.
Main Results:
- Sirt3 KO mice exhibited exacerbated age-related fibrosis across multiple organs.
- SIRT3 deficiency led to increased TGF-β1 expression and hyperacetylation of GSK3β at K15, inhibiting its activity.
- Reduced GSK3β activity resulted in increased phosphorylation and activation of Smad3 and β-catenin, promoting profibrotic gene expression.
- SIRT3 directly deacetylated and activated GSK3β, thereby suppressing TGF-β1 signaling and preventing fibrosis.
Conclusions:
- SIRT3 acts as a crucial negative regulator of age-associated tissue fibrosis.
- SIRT3 suppresses profibrotic TGF-β1 signaling by deacetylating and activating GSK3β.
- This study reveals a novel, phosphorylation-independent mechanism controlling GSK3β activity and its role in fibrosis.
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