Insulin signaling pathway protects neuronal cell lines by Sirt3 mediated IRS2 activation

Mishra, Neha and Lata, Sonam and Deshmukh, Priyanka and Kamat, Kajal and Surolia, Avadhesha and Banerjee, Tanushree (2018) Insulin signaling pathway protects neuronal cell lines by Sirt3 mediated IRS2 activation. In: BIOFACTORS, 44 (3). pp. 224-236.

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Abstract

Cellular stress like ER and oxidative stress are the principle causative agents of various proteinopathies. Multifunctional protein PARK7/DJ-1 provides protection against cellular stress. Recently, insulin/IGF also has emerged as a neuro-protective molecule. However, it is not known whether DJ-1 and insulin/IGF complement each other for cellular protection in response to stress. In this study, we show for the first time, that in human and mouse neuronal cell lines, down regulation of DJ-1 for 48 h leads to compensatory upregulation of insulin/IGF signaling (IIS) pathway genes, namely, insulin receptor, insulin receptor substrate, and Akt under normal physiological conditions as well as in cellular stress conditions. Moreover, upon exogenous supply of insulin there is a marked increase in the IIS components both at gene and protein levels leading to down regulation and inactivation of GSK3. By immunoprecipitation, it was observed that Sirt3 mediated deacetylation and activation of FoxO3a could not occur under DJ-1 downregulation. Transient DJ-1 downregulation also led to Akt mediated increased phosphorylation and nuclear exclusion of FoxO3a. When DJ-1 was downregulated increased interaction of Sirt3 with IRS2 was observed leading to its activation resulting in IIS upregulation. Thus, transient downregulation of DJ-1 leads to stimulation of IIS pathway by Sirt3 mediated IRS2 activation. Consequently, antiapoptotic program is triggered in neuronal cells via Akt-GSK3-FoxO3a axis. (c) 2018 BioFactors, 44(3):224-236, 2018

Item Type:	Journal Article
Publication:	BIOFACTORS
Publisher:	WILEY, 111 RIVER ST, HOBOKEN 07030-5774, NJ USA
Additional Information:	Copyright of this article belong to WILEY, 111 RIVER ST, HOBOKEN 07030-5774, NJ USA
Department/Centre:	Division of Biological Sciences > Molecular Biophysics Unit
Date Deposited:	17 Jul 2018 15:27
Last Modified:	17 Jul 2018 15:27
URI:	http://eprints.iisc.ac.in/id/eprint/60201

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