| First Author | Sundaresan NR | Year | 2015 |
| Journal | Mol Cell Biol | Volume | 36 |
| Issue | 5 | Pages | 678-92 |
| PubMed ID | 26667039 | Mgi Jnum | J:236133 |
| Mgi Id | MGI:5804754 | Doi | 10.1128/MCB.00586-15 |
| Citation | Sundaresan NR, et al. (2015) SIRT3 Blocks Aging-Associated Tissue Fibrosis in Mice by Deacetylating and Activating Glycogen Synthase Kinase 3beta. Mol Cell Biol 36(5):678-92 |
| abstractText | Tissue fibrosis is a major cause of organ dysfunction during chronic diseases and aging. A critical step in this process is transforming growth factor beta1 (TGF-beta1)-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-beta1 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-beta1 expression and hyperacetylation of glycogen synthase kinase 3beta (GSK3beta) at residue K15, which negatively regulated GSK3beta activity to phosphorylate the substrates Smad3 and beta-catenin. Reduced phosphorylation led to stabilization and activation of these transcription factors regulating expression of the profibrotic genes. SIRT3 deacetylated and activated GSK3beta and thereby blocked TGF-beta1 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 GSK3beta. |
