A phospho-switch at Acinus-Serine437 controls autophagic responses to Cadmium exposure and neurodegenerative stress

  1. Nilay Nandi
  2. Zuhair Zaidi
  3. Charles Tracy
  4. Helmut Krämer  Is a corresponding author
  1. The University of Texas Southwestern Medical Center, United States

Abstract

Neuronal health depends on quality control functions of autophagy, but mechanisms regulating neuronal autophagy are poorly understood. Previously, we showed that in Drosophila starvation-independent quality control autophagy is regulated by Acinus and the Cdk5-dependent phosphorylation of its serine437 (Nandi et al., 2017). Here, we identify the phosphatase that counterbalances this activity and provides for the dynamic nature of Acinus-S437 phosphorylation. A genetic screen identified six phosphatases that genetically interacted with an Acinus gain-of-function model. Among these, loss of function of only one, the PPM-type phosphatase Nil (CG6036), enhanced pS437-Acinus levels. Cdk5-dependent phosphorylation of Acinus serine437 in nil1 animals elevates neuronal autophagy and reduces the accumulation of polyQ proteins in a Drosophila Huntington's disease model. Consistent with previous findings that Cd2+ inhibits PPM-type phosphatases, Cd2+-exposure elevated Acinus-serine437 phosphorylation which was necessary for increased neuronal autophagy and protection against Cd2+-induced cytotoxicity. Together, our data establish the Acinus-S437 phospho-switch as critical integrator of multiple stress signals regulating neuronal autophagy.

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All data generated or analysed during this study are included in the manuscript and supporting files.

Article and author information

Author details

  1. Nilay Nandi

    Department of Neuroscience, The University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7088-4943
  2. Zuhair Zaidi

    Department of Neuroscience, The University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Charles Tracy

    Department of Neuroscience, The University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Helmut Krämer

    Department of Neuroscience, The University of Texas Southwestern Medical Center, Dallas, United States
    For correspondence
    helmut.kramer@utsouthwestern.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1167-2676

Funding

National Eye Institute (R01EY010199)

  • Helmut Krämer

National Eye Institute (R21EY030785)

  • Helmut Krämer

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

Copyright

© 2022, Nandi 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. Nilay Nandi
  2. Zuhair Zaidi
  3. Charles Tracy
  4. Helmut Krämer
(2022)
A phospho-switch at Acinus-Serine437 controls autophagic responses to Cadmium exposure and neurodegenerative stress
eLife 11:e72169.
https://doi.org/10.7554/eLife.72169

Share this article

https://doi.org/10.7554/eLife.72169

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