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

Veronica Cloud1, Ada Thapa1, Pedro Morales-Sosa1

  • 1University of Missouri - Kansas City, Kansas City, United States.

Elife
|July 27, 2019
PubMed

Insights

Polyglutamine expansion in Atxn7 causes spinocerebellar ataxia type 7 (SCA7). The deubiquitinase Non-stop, when free from Atxn7, regulates actin cytoskeleton assembly by stabilizing SCAR protein levels.

Area of Science:

  • Molecular Biology
  • Neurogenetics
  • Cell Biology

Background:

  • Atxn7 (Ataxin-7) is a subunit of the SAGA chromatin remodeling complex.
  • Polyglutamine expansion in Atxn7 causes spinocerebellar ataxia type 7 (SCA7), a neurodegenerative disease.
  • Atxn7's amino terminus anchors the deubiquitinase Non-stop to the SAGA complex.

Purpose of the Study:

  • To investigate the substrates and functions of Non-stop when dissociated from Atxn7.
  • To understand the role of the Atxn7-Non-stop interaction in cellular regulation.

Main Methods:

  • Proteomic screening to identify Non-stop substrates.
  • Co-immunoprecipitation to study protein interactions.
  • Cellular assays to assess actin cytoskeleton dynamics and cell morphology.
  • In vivo genetic manipulation in model organisms.

Main Results:

  • Non-stop, when dissociated from Atxn7, interacts with Arp2/3 and WAVE regulatory complexes (WRC).
  • Non-stop deubiquitinates and stabilizes SCAR, a WRC subunit, counteracting its proteasomal degradation.
  • Non-stop activity influences SCAR protein levels and subcellular localization, affecting cell area and protrusions.
  • In vivo, Atxn7 mutation can rescue SCAR haploinsufficiency, suggesting functional interplay.

Conclusions:

  • The Atxn7 amino terminus sequesters Non-stop, modulating its interaction with the actin cytoskeleton machinery.
  • Non-stop plays a critical role in regulating SCAR stability and actin dynamics, independent of its association with Atxn7.
  • Dysregulation of the Non-stop-SCAR axis may contribute to the pathogenesis of SCA7 and related disorders.
Keywords:
Ataxin7D. melanogasterNon-stopSAGA complexWAVE regulatory complexactincell biologyneurobiologyneuroscience

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