SIRT2 deacetylase represses NFAT transcription factor to maintain cardiac homeostasis

Sarikhani, Mohsen and Maity, Sangeeta and Mishra, Sneha and Jain, Aditi and Tamta, Ankit K and Ravi, Venkatraman and Kondapalli, Mrudula S and Desingu, Perumal A and Khan, Danish and Kumar, Shweta and Rao, Swathi and Inbaraj, Meena and Pandit, Anwit S and Sundaresan, Nagalingam Ravi (2018) SIRT2 deacetylase represses NFAT transcription factor to maintain cardiac homeostasis. In: JOURNAL OF BIOLOGICAL CHEMISTRY, 293 (14). pp. 5281-5294.

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Abstract

Heart failure is an aging-associated disease that is the leading cause of death worldwide. Sirtuin family members have been largely studied in the context of aging and aging-associated diseases. Sirtuin 2 (SIRT2) is a cytoplasmic protein in the family of sirtuins that are NAD(+)-dependent class III histone deacetylases. In this work, we studied the role of SIRT2 in regulating nuclear factor of activated T-cells (NFAT) transcription factor and the development of cardiac hypertrophy. Confocal microscopy analysis indicated that SIRT2 is localized in the cytoplasm of cardiomyocytes and SIRT2 levels are reduced during pathological hypertrophy of the heart. SIRT2-deficient mice develop spontaneous pathological cardiac hypertrophy, remodeling, fibrosis, and dysfunction in an age-dependent manner. Moreover, young SIRT2-deficient mice develop exacerbated agonist-induced hypertrophy. In contrast, SIRT2 overexpression attenuated agonist-induced cardiac hypertrophy in cardiomyocytes in a cell-autonomous manner. Mechanistically, SIRT2 binds to and deacetylates NFATc2 transcription factor. SIRT2 deficiency stabilizes NFATc2 and enhances nuclear localization of NFATc2, resulting in increased transcription activity. Our results suggest that inhibition of NFAT rescues the cardiac dysfunction in SIRT2-deficient mice. Thus, our study establishes SIRT2 as a novel endogenous negative regulator of NFAT transcription factor.

Item Type:	Journal Article
Publication:	JOURNAL OF BIOLOGICAL CHEMISTRY
Publisher:	AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC, 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA
Additional Information:	Copy right for this article belong to AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC, 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA
Department/Centre:	Division of Biological Sciences > Microbiology & Cell Biology
Date Deposited:	04 May 2018 18:48
Last Modified:	04 May 2018 18:48
URI:	http://eprints.iisc.ac.in/id/eprint/59737

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