Format

Send to

Choose Destination
Mol Cell Biol. 2015 Dec 14;36(5):678-92. doi: 10.1128/MCB.00586-15.

SIRT3 Blocks Aging-Associated Tissue Fibrosis in Mice by Deacetylating and Activating Glycogen Synthase Kinase 3β.

Author information

1
Department of Surgery, Biological Science Division, University of Chicago, Chicago, Illinois, USA.
2
Gladstone Institutes, University of California, San Francisco, San Francisco, California, USA.
3
Department of Physiology and Biophysics, University of Illinois at Chicago, Chicago, Illinois, USA.
4
Department of Molecular Genetics and Cell Biology, University of Chicago, Chicago, Illinois, USA.
5
Gladstone Institutes, University of California, San Francisco, San Francisco, California, USA everdin@gladstone.ucsf.edu mgupta@surgery.bsd.uchicago.edu.
6
Department of Surgery, Biological Science Division, University of Chicago, Chicago, Illinois, USA Committee on Molecular Pathology and Molecular Medicine, University of Chicago, Chicago, Illinois, USA everdin@gladstone.ucsf.edu mgupta@surgery.bsd.uchicago.edu.

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.

PMID:
26667039
PMCID:
PMC4760222
DOI:
10.1128/MCB.00586-15
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center