1. Cell Biology

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

  1. Mohsen Sarikhani
  2. Sneha Mishra
  3. Sangeeta Maity
  4. Chaithanya Kotyada
  5. Donald Wolfgeher
  6. Mahesh P Gupta
  7. Mahavir Singh
  8. Nagalingam R Sundaresan  Is a corresponding author
  1. Indian Institute of Science, India
  2. University of Chicago, United States
https://doi.org/10.7554/eLife.32952
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Cite this article
  1. Mohsen Sarikhani
  2. Sneha Mishra
  3. Sangeeta Maity
  4. Chaithanya Kotyada
  5. Donald Wolfgeher
  6. Mahesh P Gupta
  7. Mahavir Singh
  8. Nagalingam R Sundaresan
(2018)
SIRT2 deacetylase regulates the activity of GSK3 isoforms independent of inhibitory phosphorylation
eLife 7:e32952.
https://doi.org/10.7554/eLife.32952
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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 GSK3α and GSK3β 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 GSK3β, and thus enhances its binding to ATP. Interestingly, the reduced activity of GSK3β 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.

Article and author information

Author details

  1. Mohsen Sarikhani

    Department of Microbiology and Cell Biology, Indian Institute of Science, Bengaluru, India
    Competing interests
    The authors declare that no competing interests exist.

  2. Sneha Mishra

    Department of Microbiology and Cell Biology, Indian Institute of Science, Bengaluru, India
    Competing interests
    The authors declare that no competing interests exist.

  3. Sangeeta Maity

    Department of Microbiology and Cell Biology, Indian Institute of Science, Bengaluru, India
    Competing interests
    The authors declare that no competing interests exist.

  4. Chaithanya Kotyada

    Molecular Biophysics Unit, Indian Institute of Science, Bengaluru, India
    Competing interests
    The authors declare that no competing interests exist.

  5. Donald Wolfgeher

    Department of Molecular Genetics and Cell biology, University of Chicago, Chicago, United States
    Competing interests
    The authors declare that no competing interests exist.

  6. Mahesh P Gupta

    Department of Surgery, University of Chicago, Chicago, United States
    Competing interests
    The authors declare that no competing interests exist.

  7. Mahavir Singh

    Molecular Biophysics Unit, Indian Institute of Science, Bengaluru, India
    Competing interests
    The authors declare that no competing interests exist.

  8. Nagalingam R Sundaresan

    Department of Microbiology and Cell Biology, Indian Institute of Science, Bengaluru, India
    For correspondence
    rsundaresan@iisc.ac.in
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1770-5616

Funding

Department of Biotechnology , Ministry of Science and Technology (BRB/10/1294/2014)

  • Nagalingam R Sundaresan

Department of Biotechnology , Ministry of Science and Technology (MED/30/1454/2014)

  • Nagalingam R Sundaresan

Department of Biotechnology , Ministry of Science and Technology (IYBA Award)

  • Nagalingam R Sundaresan

Department of Biotechnology , Ministry of Science and Technology (Ramalingaswami fellowship)

  • Nagalingam R Sundaresan

Department of Science and Technology, Ministry of Science and Technology (EMR/2014/000065)

  • Nagalingam R Sundaresan

Council of Scientific and Industrial Research (37(1646)/15/EMR-II)

  • Nagalingam R Sundaresan

Department of Science and Technology, Ministry of Science and Technology (N-PDF)

  • Sangeeta Maity

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Roger J Davis, University of Massachusetts Medical School, United States

Ethics

Animal experimentation: All animal experiments were performed with the approval of Institutional animal ethics committee of Indian institute of science, Bengaluru, India. All the animal experiments were carried out as per the strict accordance with the recommendations of the Committee for the Purpose of Control and Supervision of Experiments on Animals (CPCSEA), Government of India. The protocols were approved by the Institutional Animal Ethics Committee of the Indian Institute of Science (Permit Numbers: 559/2017, 568/2017, 376/2014 ). Mice were sacrificed using CO2 before harvesting and every effort was made to minimize suffering.

Version history

  1. Received: October 19, 2017
  2. Accepted: March 2, 2018
  3. Accepted Manuscript published: March 5, 2018 (version 1)
  4. Version of Record published: March 20, 2018 (version 2)

Copyright

© 2018, Sarikhani et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Mohsen Sarikhani
  2. Sneha Mishra
  3. Sangeeta Maity
  4. Chaithanya Kotyada
  5. Donald Wolfgeher
  6. Mahesh P Gupta
  7. Mahavir Singh
  8. Nagalingam R Sundaresan
(2018)
SIRT2 deacetylase regulates the activity of GSK3 isoforms independent of inhibitory phosphorylation
eLife 7:e32952.
https://doi.org/10.7554/eLife.32952

Share this article

https://doi.org/10.7554/eLife.32952

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