Specific RNA interactions promote TDP-43 multivalent phase separation and maintain liquid properties

Zachary R. Grese, Alliny C.S. Bastos, Lohany D. Mamede, Rachel L. French, Timothy M. Miller, Yuna M. Ayala

Research output: Contribution to journalArticlepeer-review

11 Scopus citations

Abstract

TDP-43 is an RNA-binding protein that forms ribonucleoprotein condensates via liquid-liquid phase separation (LLPS) and regulates gene expression through specific RNA interactions. Loss of TDP-43 protein homeostasis and dysfunction are tied to neurodegenerative disorders, mainly amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. Alterations of TDP-43 LLPS properties may be linked to protein aggregation. However, the mechanisms regulating TDP-43 LLPS are ill-defined, particularly how TDP-43 association with specific RNA targets regulates TDP-43 condensation remains unclear. We show that RNA binding strongly promotes TDP-43 LLPS through sequence-specific interactions. RNA-driven condensation increases with the number of adjacent TDP-43-binding sites and is also mediated by multivalent interactions involving the amino and carboxy-terminal TDP-43 domains. The physiological relevance of RNA-driven TDP-43 condensation is supported by similar observations in mammalian cellular lysate. Importantly, we find that TDP-43-RNA association maintains liquid-like properties of the condensates, which are disrupted in the presence of ALS-linked TDP-43 mutations. Altogether, RNA binding plays a central role in modulating TDP-43 condensation while maintaining protein solubility, and defects in this RNA-mediated activity may underpin TDP-43-associated pathogenesis.

Original languageEnglish
Article numbere53632
JournalEMBO Reports
Volume22
Issue number12
DOIs
StatePublished - Dec 6 2021

Keywords

  • RNA-binding protein
  • TDP-43
  • amyotrophic lateral sclerosis
  • liquid-liquid phase separation
  • ribonucleoprotein (RNP) granules

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