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

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Title: SIRT3 Blocks Aging-Associated Tissue Fibrosis in Mice by Deacetylating and Activating Glycogen Synthase Kinase 3β.
Author(s): Sundaresan, N. R; Bindu, S.; Pillai, V. B.; Samant, S.; Pan, Y.; Huang, J. Y.; Gupta, M.; Nagalingam, R. S.; Wolfgeher, D.; Verdin, E.; Gupta, M. P.
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 beta 1 (TGF-beta 1)-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-beta 1 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-beta 1 expression and hyperacetylation of glycogen synthase kinase 3 beta(GSK3 beta) at residue K15, which negatively regulated GSK3 beta 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 GSK3 beta and thereby blocked TGF-beta 1 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 GSK3 beta.
Issue Date: 2016-03
Publisher: American Society for Microbiology
Citation Info: Sundaresan, Nagalingam R., Samik Bindu, Vinodkumar B. Pillai, Sadhana Samant, Yong Pan, Jing-Yi Huang, Madhu Gupta et al. "SIRT3 blocks aging-associated tissue fibrosis in mice by deacetylating and activating glycogen synthase kinase 3β." Molecular and cellular biology 36, no. 5 (2016): 678-692. DOI: 10.1128/MCB.00586-15
Type: Article
Description: This is a copy of an article published in Molecular and Cellular Biology. © 2016 American Society for Microbiology Publications.
URI: http://hdl.handle.net/10027/21038
ISSN: 0270-7306
Sponsor: HHS | NIH | National Heart, Lung, and Blood Institute (NHLBI) provided funding to Mahesh P. Gupta under grant number RO1 HL117041. HHS | NIH | National Heart, Lung, and Blood Institute (NHLBI) provided funding to Mahesh P. Gupta under grant number RO1 HL111455.
Date Available in INDIGO: 2016-08-08
 

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