Poly(A)-Binding Protein Is an Ataxin-2 Chaperone That Regulates Biomolecular Condensates

Authors

Steven Boeynaems
Yanniv Dorone
Yanrong Zhuang
Victoria Shabardina
Guozhong Huang
Anca Marian
Garam Kim
Anushka Sanyal
Nesli-Ece Şen
Daniel Griffith
Roberto Docampo
Keren Lasker
Iñaki Ruiz-Trillo
Georg Auburger
Alex S Holehouse
Edor Kabashi
Yi Lin
Aaron D Gitler

Publication Date

6-15-2023

Journal

Molecular Cell

DOI

10.1016/j.molcel.2023.05.025

PMID

37295429

PMCID

PMC10318123

PubMedCentral® Posted Date

6-15-2024

PubMedCentral® Full Text Version

Author MSS

Published Open-Access

yes

Keywords

Humans, Ataxin-2, Poly(A)-Binding Protein I, Neurodegenerative Diseases, Biomolecular Condensates, Protein phase separation, short linear motif, polyQ, protein aggregation, PABPC, stress granules, ATXN2, amyotrophic lateral sclerosis, spinocerebellar ataxia, microtubule-binding protein

Abstract

Biomolecular condensation underlies the biogenesis of an expanding array of membraneless assemblies, including stress granules (SGs), which form under a variety of cellular stresses. Advances have been made in understanding the molecular grammar of a few scaffold proteins that make up these phases, but how the partitioning of hundreds of SG proteins is regulated remains largely unresolved. While investigating the rules that govern the condensation of ataxin-2, an SG protein implicated in neurodegenerative disease, we unexpectedly identified a short 14 aa sequence that acts as a condensation switch and is conserved across the eukaryote lineage. We identify poly(A)-binding proteins as unconventional RNA-dependent chaperones that control this regulatory switch. Our results uncover a hierarchy of cis and trans interactions that fine-tune ataxin-2 condensation and reveal an unexpected molecular function for ancient poly(A)-binding proteins as regulators of biomolecular condensate proteins. These findings may inspire approaches to therapeutically target aberrant phases in disease.