title: SIRT3 Blocks Aging-Associated Tissue Fibrosis in Mice by Deacetylating and Activating Glycogen Synthase Kinase 3β.
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.
authors.affiliation: Department of Surgery, Biological Science Division, University of Chicago, Chicago, Illinois, USA.
authors.forename: Nagalingam R
authors.initials: NR
authors.lastname: Sundaresan
authors.affiliation: Department of Surgery, Biological Science Division, University of Chicago, Chicago, Illinois, USA.
authors.forename: Samik
authors.initials: S
authors.lastname: Bindu
authors.affiliation: Department of Surgery, Biological Science Division, University of Chicago, Chicago, Illinois, USA.
authors.forename: Vinodkumar B
authors.initials: VB
authors.lastname: Pillai
authors.affiliation: Department of Surgery, Biological Science Division, University of Chicago, Chicago, Illinois, USA.
authors.forename: Sadhana
authors.initials: S
authors.lastname: Samant
authors.affiliation: Gladstone Institutes, University of California, San Francisco, San Francisco, California, USA.
authors.forename: Yong
authors.initials: Y
authors.lastname: Pan
authors.affiliation: Gladstone Institutes, University of California, San Francisco, San Francisco, California, USA.
authors.forename: Jing-Yi
authors.initials: JY
authors.lastname: Huang
authors.affiliation: Department of Physiology and Biophysics, University of Illinois at Chicago, Chicago, Illinois, USA.
authors.forename: Madhu
authors.initials: M
authors.lastname: Gupta
authors.affiliation: Department of Physiology and Biophysics, University of Illinois at Chicago, Chicago, Illinois, USA.
authors.forename: Raghu S
authors.initials: RS
authors.lastname: Nagalingam
authors.affiliation: Department of Molecular Genetics and Cell Biology, University of Chicago, Chicago, Illinois, USA.
authors.forename: Donald
authors.initials: D
authors.lastname: Wolfgeher
authors.affiliation: Gladstone Institutes, University of California, San Francisco, San Francisco, California, USA everdin@gladstone.ucsf.edu mgupta@surgery.bsd.uchicago.edu.
authors.forename: Eric
authors.initials: E
authors.lastname: Verdin
authors.affiliation: 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.
authors.forename: Mahesh P
authors.initials: MP
authors.lastname: Gupta
mesh_terms: D000107:Acetylation; D000328:Adult; D000375:Aging; D000818:Animals; D002478:Cells, Cultured; D004789:Enzyme Activation; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism / Q000473:pathology*; D005355:Fibrosis; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D007668:Kidney / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D008099:Liver / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009206:Myocardium / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D058628:Myofibroblasts / Q000166:cytology / Q000378:metabolism / Q000473:pathology*; D010766:Phosphorylation; D015398:Signal Transduction; D056566:Sirtuin 3 / Q000235:genetics / Q000378:metabolism*; D051900:Smad3 Protein / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism
chemical_list: C525046:Sirt3 protein, mouse; D051900:Smad3 Protein; D053773:Transforming Growth Factor beta1; D051176:beta Catenin; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3; D056566:Sirtuin 3