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SIRT2 deacetylase regulates the activity of GSK3 isoforms independent of inhibitory phosphorylation

Sarikhani, Mohsen and Mishra, Sneha and Maity, Sangeeta and Kotyada, Chaithanya and Wolfgeher, Donald and Gupta, Mahesh P and Singh, Mahavir and Sundaresan, Nagalingam R (2018) SIRT2 deacetylase regulates the activity of GSK3 isoforms independent of inhibitory phosphorylation. In: ELIFE, 7 .

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Official URL: http://dx.doi.org/10.7554/eLife.32952

Abstract

Glycogen synthase kinase 3 (GSK3) is a critical regulator of diverse cellular functions involved in the maintenance of structure and function. Enzymatic activity of GSK3 is inhibited by N-terminal serine phosphorylation. However, alternate post-translational mechanism(s) responsible for GSK3 inactivation are not characterized. Here, we report that GSK3 alpha and GSK3 beta are acetylated at Lys246 and Lys183, respectively. Molecular modeling and/or molecular dynamics simulations indicate that acetylation of GSK3 isoforms would hinder both the adenosine binding and prevent stable interactions of the negatively charged phosphates. We found that SIRT2 deacetylates GSK3 beta, and thus enhances its binding to ATP. Interestingly, the reduced activity of GSK3 beta is associated with lysine acetylation, but not with phosphorylation at Ser9 in hearts of SIRT2-deficient mice. Moreover, GSK3 is required for the anti-hypertrophic function of SIRT2 in cardiomyocytes. Overall, our study identified lysine acetylation as a novel post-translational modification regulating GSK3 activity.

Item Type: Journal Article
Additional Information: Copy right for the article belong to ELIFE SCIENCES PUBLICATIONS LTD, SHERATON HOUSE, CASTLE PARK, CAMBRIDGE, CB3 0AX, ENGLAND
Department/Centre: Division of Biological Sciences > Molecular Biophysics Unit
Division of Biological Sciences > Microbiology & Cell Biology
Depositing User: Id for Latest eprints
Date Deposited: 12 Apr 2018 18:48
Last Modified: 12 Apr 2018 18:48
URI: http://eprints.iisc.ac.in/id/eprint/59530

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