The phase separation-dependent FUS interactome reveals nuclear and cytoplasmic function of liquid-liquid phase separation.
Journal
Nucleic acids research
ISSN: 1362-4962
Titre abrégé: Nucleic Acids Res
Pays: England
ID NLM: 0411011
Informations de publication
Date de publication:
21 07 2021
21 07 2021
Historique:
accepted:
28
06
2021
revised:
15
06
2021
received:
09
11
2019
pubmed:
8
7
2021
medline:
10
8
2021
entrez:
7
7
2021
Statut:
ppublish
Résumé
Liquid-liquid phase separation (LLPS) of proteins and RNAs has emerged as the driving force underlying the formation of membrane-less organelles. Such biomolecular condensates have various biological functions and have been linked to disease. The protein Fused in Sarcoma (FUS) undergoes LLPS and mutations in FUS have been causally linked to the motor neuron disease Amyotrophic Lateral Sclerosis (ALS-FUS). LLPS followed by aggregation of cytoplasmic FUS has been proposed to be a crucial disease mechanism. However, it is currently unclear how LLPS impacts the behaviour of FUS in cells, e.g. its interactome. Hence, we developed a method allowing for the purification of LLPS FUS-containing droplets from cell lysates. We observe substantial alterations in the interactome, depending on its biophysical state. While non-LLPS FUS interacts mainly with factors involved in pre-mRNA processing, LLPS FUS predominantly binds to proteins involved in chromatin remodelling and DNA damage repair. Interestingly, also mitochondrial factors are strongly enriched with LLPS FUS, providing a potential explanation for the observed changes in mitochondrial gene expression in mouse models of ALS-FUS. In summary, we present a methodology to investigate the interactomes of phase separating proteins and provide evidence that LLPS shapes the FUS interactome with implications for function and disease.
Identifiants
pubmed: 34233002
pii: 6316831
doi: 10.1093/nar/gkab582
pmc: PMC8287939
doi:
Substances chimiques
Chromatin
0
RNA, Messenger
0
RNA, Small Nuclear
0
RNA-Binding Protein FUS
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
7713-7731Subventions
Organisme : Medical Research Council
ID : MR/S025898/1
Pays : United Kingdom
Informations de copyright
© The Author(s) 2021. Published by Oxford University Press on behalf of Nucleic Acids Research.
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