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

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...

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Bibliographic Details
Published in:EMBO reports 2021-12, Vol.22 (12), p.e53632-n/a
Main Authors: Grese, Zachary R, Bastos, Alliny CS, Mamede, Lohany D, French, Rachel L, Miller, Timothy M, Ayala, Yuna M
Format: Article
Language:English
Subjects:
Amyotrophic lateral sclerosis
Amyotrophic Lateral Sclerosis - genetics
Amyotrophic Lateral Sclerosis - metabolism
Animals
Binding sites
Condensates
Condensation
Dementia disorders
DNA-Binding Proteins - metabolism
Domains
Frontotemporal dementia
Frontotemporal Dementia - genetics
Gene expression
Gene sequencing
Homeostasis
Liquid phases
Liquidity
liquid‐liquid phase separation
Mutation
Neurodegenerative diseases
Nucleotide sequence
Pathogenesis
Phase separation
Protein interaction
Proteins
Ribonucleic acid
ribonucleoprotein (RNP) granules
RNA
RNA - genetics
RNA-Binding Proteins - genetics
RNA‐binding protein
TDP‐43
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Summary: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. SYNOPSIS Liquid‐liquid phase separation of the RNA‐binding protein TDP‐43 is regulated by specific RNA sequences. In addition to modulating phase separation, RNA is crucial for maintaining the liquid state of TDP‐43 condensates. GU‐repeat RNA specifically promotes TDP‐43 liquid‐liquid phase separation and this increases with multiple binding sites. Binding of specific RNA sequences to the TDP‐43 RNA‐binding domains maintains liquidity of TDP‐43 condensates. Both the N‐ and C‐terminal TDP‐43 domains are required for RNA‐driven liquid‐liquid phase separation, constituting a multivalent network. The liquid properties of RNA‐driven TDP‐43 condensates are disrupted in a subset of ALS‐linked TDP‐43 mutations. Liquid‐liquid phase separation of the RNA‐binding protein TDP‐43 is regulated by specific RNA sequences. In addition to modulating phase separation, RNA is crucial for maintaining the liquid state of TDP‐43 condensates.
ISSN:1469-221X
1469-3178
DOI:10.15252/embr.202153632