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

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posted on 08.08.2016 by N. R Sundaresan, S. Bindu, V. B. Pillai, S. Samant, Y. Pan, J. Y. Huang, M. Gupta, R. S. Nagalingam, D. Wolfgeher, E. Verdin, M. P. Gupta
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.

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Funding

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.

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Publisher Statement

This is a copy of an article published in Molecular and Cellular Biology. © 2016 American Society for Microbiology Publications.

Publisher

American Society for Microbiology

Language

en_US

issn

0270-7306

Issue date

01/03/2016

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