Ataxin-7 and Non-stop coordinate SCAR protein levels, subcellular localization, and actin cytoskeleton organization

Abstract

Atxn7, a subunit of SAGA chromatin remodeling complex, is subject to polyglutamine expansion at the amino terminus, causing spinocerebellar ataxia type 7 (SCA7), a progressive retinal and neurodegenerative disease. Within SAGA, the Atxn7 amino terminus anchors Non-stop, a deubiquitinase, to the complex. To understand the scope of Atxn7-dependent regulation of Non-stop, substrates of the deubiquitinase were sought. This revealed Non-stop, dissociated from Atxn7, interacts with Arp2/3 and WAVE regulatory complexes (WRC), which control actin cytoskeleton assembly. There, Non-stop countered polyubiquitination and proteasomal degradation of WRC subunit SCAR. Dependent on conserved WRC interacting receptor sequences (WIRS), Non-stop augmentation increased protein levels, and directed subcellular localization, of SCAR, decreasing cell area and number of protrusions. In vivo, heterozygous mutation of Atxn7 rescued haploinsufficiency of SCAR, but heterozygous mutation of SCAR did not significantly rescue knockdown of Atxn7.

Data availability

All proteomics data are available in the MassIVE repository. The permanent URL to the dataset is: ftp://massive.ucsd.edu/MSV000082625. The data is also accessible from: ProteomeXChange accession: PXD010462 http://proteomecentral.proteomexchange.org/cgi/GetDataset?ID=PXD010462. MassIVE | Accession ID: MSV000082625 - ProteomeXchange | Accession ID: PXD010462

The following data sets were generated

Article and author information

Author details

  1. Veronica Cloud

    School of Biological Sciences, University of Missouri - Kansas City, Kansas City, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Ada Thapa

    School of Biological and Chemical Sciences, University of Missouri - Kansas City, Kansas City, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Pedro Morales-Sosa

    School of Biological and Chemical Sciences, University of Missouri - Kansas City, Kansas City, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Tayla Miller

    School of Biological and Chemical Sciences, University of Missouri - Kansas City, Kansas City, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Sara A Miller

    School of Biological Sciences, University of Missouri - Kansas City, Kansas City, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Daniel Holsapple

    School of Biological Sciences, University of Missouri - Kansas City, Kansas City, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Paige Gerhart

    School of Biological and Chemical Sciences, University of Missouri - Kansas City, Kansas City, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Elaheh Momtahan

    School of Biological Sciences, University of Missouri - Kansas City, Kansas City, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Jarrid L Jack

    School of Biological Sciences, University of Missouri - Kansas City, Kansas City, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Edgardo Leiva

    School of Biological Sciences, University of Missouri - Kansas City, Kansas City, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. Sarah R Rapp

    School of Biological Sciences, University of Missouri - Kansas City, Kansas City, United States
    Competing interests
    The authors declare that no competing interests exist.
  12. Lauren G Shelton

    Stowers Institute for Medical Research, Kansas City, United States
    Competing interests
    The authors declare that no competing interests exist.
  13. Richard A Pierce

    School of Biological and Chemical Sciences, University of Missouri - Kansas City, Kansas City, United States
    Competing interests
    The authors declare that no competing interests exist.
  14. Skylar Martin-Brown

    Stowers Institute for Medical Research, Kansas City, United States
    Competing interests
    The authors declare that no competing interests exist.
  15. Laurence Florens

    Stowers Institute for Medical Research, Kansas City, United States
    Competing interests
    The authors declare that no competing interests exist.
  16. Michael P Washburn

    Stowers Institute for Medical Research, Kansas City, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7568-2585
  17. Ryan D Mohan

    School of Biological and Chemical Sciences, University of Missouri - Kansas City, Kansas City, United States
    For correspondence
    Mohanrd@umkc.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7624-4605

Funding

National Institutes of Health (NIGMS grant 5R35GM118068)

  • Ryan D Mohan

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

Copyright

© 2019, Cloud 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.

Metrics

  • 2,503
    views
  • 282
    downloads
  • 15
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Veronica Cloud
  2. Ada Thapa
  3. Pedro Morales-Sosa
  4. Tayla Miller
  5. Sara A Miller
  6. Daniel Holsapple
  7. Paige Gerhart
  8. Elaheh Momtahan
  9. Jarrid L Jack
  10. Edgardo Leiva
  11. Sarah R Rapp
  12. Lauren G Shelton
  13. Richard A Pierce
  14. Skylar Martin-Brown
  15. Laurence Florens
  16. Michael P Washburn
  17. Ryan D Mohan
(2019)
Ataxin-7 and Non-stop coordinate SCAR protein levels, subcellular localization, and actin cytoskeleton organization
eLife 8:e49677.
https://doi.org/10.7554/eLife.49677

Share this article

https://doi.org/10.7554/eLife.49677

Further reading

    1. Cell Biology
    Yan Song, Linda J Fothergill ... Gene W Yeo
    Research Article

    Dynamic interactions between gut mucosal cells and the external environment are essential to maintain gut homeostasis. Enterochromaffin (EC) cells transduce both chemical and mechanical signals and produce 5-hydroxytryptamine to mediate disparate physiological responses. However, the molecular and cellular basis for functional diversity of ECs remains to be adequately defined. Here, we integrated single-cell transcriptomics with spatial image analysis to identify 14 EC clusters that are topographically organized along the gut. Subtypes predicted to be sensitive to the chemical environment and mechanical forces were identified that express distinct transcription factors and hormones. A Piezo2+ population in the distal colon was endowed with a distinctive neuronal signature. Using a combination of genetic, chemogenetic, and pharmacological approaches, we demonstrated Piezo2+ ECs are required for normal colon motility. Our study constructs a molecular map for ECs and offers a framework for deconvoluting EC cells with pleiotropic functions.

    1. Cell Biology
    2. Developmental Biology
    Sarah Y Coomson, Salil A Lachke
    Insight

    A study in mice reveals key interactions between proteins involved in fibroblast growth factor signaling and how they contribute to distinct stages of eye lens development.