Antagonistic roles for Ataxin-2 structured and disordered domains in RNP condensation

Elife. 2021 Mar 10;10:e60326. doi: 10.7554/eLife.60326.

Abstract

Ataxin-2 (Atx2) is a translational control molecule mutated in spinocerebellar ataxia type II and amyotrophic lateral sclerosis. While intrinsically disordered domains (IDRs) of Atx2 facilitate mRNP condensation into granules, how IDRs work with structured domains to enable positive and negative regulation of target mRNAs remains unclear. Using the Targets of RNA-Binding Proteins Identified by Editing technology, we identified an extensive data set of Atx2-target mRNAs in the Drosophila brain and S2 cells. Atx2 interactions with AU-rich elements in 3'UTRs appear to modulate stability/turnover of a large fraction of these target mRNAs. Further genomic and cell biological analyses of Atx2 domain deletions demonstrate that Atx2 (1) interacts closely with target mRNAs within mRNP granules, (2) contains distinct protein domains that drive or oppose RNP-granule assembly, and (3) has additional essential roles outside of mRNP granules. These findings increase the understanding of neuronal translational control mechanisms and inform strategies for Atx2-based interventions under development for neurodegenerative disease.

Keywords: Ataxin-2; D. melanogaster; TRIBE; cell biology; mRNA; neurodegeneration; neuroscience; rnp granule; translational control.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Ataxin-2 / genetics*
  • Ataxin-2 / metabolism
  • Drosophila Proteins / genetics*
  • Drosophila Proteins / metabolism
  • Drosophila melanogaster / genetics*
  • Drosophila melanogaster / metabolism
  • RNA, Messenger / metabolism*
  • RNA-Binding Proteins / genetics
  • RNA-Binding Proteins / metabolism

Substances

  • ATX2 protein, Drosophila
  • Ataxin-2
  • Drosophila Proteins
  • RNA, Messenger
  • RNA-Binding Proteins

Associated data

  • GEO/GSE153985
  • GEO/GSM2065948