TitleAntagonistic roles for Ataxin-2 structured and disordered domains in RNP condensation.
Publication TypeJournal Article
Year of Publication2021
AuthorsSingh A, Hulsmeier J, Kandi AReddy, Pothapragada SShruti, Hillebrand J, Petrauskas A, Agrawal K, Rt K, Thiagarajan D, Jayaprakashappa D, VijayRaghavan K, Ramaswami M, Bakthavachalu B
JournalElife
Volume10
Date Published2021 Mar 10
ISSN2050-084X
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 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.

DOI10.7554/eLife.60326
Alternate JournalElife
PubMed ID33689682
Grant ListNCBS-TIFR Core funding / / National Centre for Biological Sciences /
SB/YS/LS-194/2014 / / Science and Engineering Research Board /
INSA/SP/YSP/143/2017 / / Indian National Science Academy /
Vajra award / / Science and Engineering Research Board /
INSPIRE Fellowship / / Department of Science and Technology, Ministry of Science and Technology /
IA/1/19/1/504286 / / Wellcome Trust/DBT India Alliance /
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