Sirtuin 6 deficiency transcriptionally up-regulates TGF-β signaling and induces fibrosis in mice

Maity, S and Muhamed, J and Sarikhani, M and Kumar, S and Ahamed, F and Spurthi, KM and Ravi, V and Jain, A and Khan, D and Arathi, BP and Desingu, PA and Sundaresan, NR (2020) Sirtuin 6 deficiency transcriptionally up-regulates TGF-β signaling and induces fibrosis in mice. In: Journal of Biological Chemistry, 295 (2). pp. 415-434.

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Abstract

Caloric restriction has been associated with increased life span and reduced aging-related disorders and reduces fibrosis in several diseases. Fibrosis is characterized by deposition of excess fibrous material in tissues and organs and is caused by aging, chronic stress, injury, or disease. Myofibroblasts are fibroblast-like cells that secrete high levels of extracellular matrix proteins, resulting in fibrosis. Histological studies have identified many-fold increases of myofibroblasts in aged organs where myofibroblasts are constantly generated from resident tissue fibroblasts and other cell types. However, it remains unclear how aging increases the generation of myofibroblasts. Here, using mouse models and biochemical assays, we show that sirtuin 6 (SIRT6) deficiency plays a major role in aging-associated transformation of fibroblasts to myofibroblasts, resulting in tissue fibrosis. Our findings suggest that SIRT6-deficient fibroblasts transform spontaneously to myofibroblasts through hyperactivation of transforming growth factor β (TGF-β) signaling in a cell-autonomous manner. Importantly, we noted that SIRT6 haploinsufficiency is sufficient for enhancing myofibroblast generation, leading to multiorgan fibrosis and cardiac dysfunction in mice during aging. Mechanistically, SIRT6 bound to and repressed the expression of key TGF-β signaling genes by deacetylating SMAD family member 3 (SMAD3) and Lys-9 and Lys-56 in histone 3. SIRT6 binding to the promoters of genes in the TGF-β signaling pathway decreased significantly with age and was accompanied by increased binding of SMAD3 to these promoters. Our findings reveal that SIRT6 may be a potential candidate for modulating TGF-β signaling to reduce multiorgan fibrosis during aging and fibrosis-associated diseases.

Item Type:	Journal Article
Publication:	Journal of Biological Chemistry
Publisher:	The American Society for Biochemistry and Molecular Biology, Inc.
Additional Information:	Copyright of this article belongs to ASBMB
Keywords:	Cell culture; Fibroblasts; Genes; Mammals; Proteins; Signaling; Tissue, Biochemical assay; Caloric restriction; Extracellular matrix protein; Fibrous material; Hyperactivation; Increased life spans; Signaling pathways; Transforming growth factor beta, Cell signaling
Department/Centre:	Division of Biological Sciences > Microbiology & Cell Biology Division of Interdisciplinary Sciences > Centre for Biosystems Science and Engineering
Date Deposited:	03 Feb 2020 09:57
Last Modified:	03 Feb 2020 09:57
URI:	http://eprints.iisc.ac.in/id/eprint/64400

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