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RNA buffers the phase separation behavior of prion-like RNA binding proteins

Title
RNA buffers the phase separation behavior of prion-like RNA binding proteins
Authors
Maharana, ShovamayeeWang, JiePapadopoulos, Dimitrios K.Richter, DorisPozniakovsky, AndreyPoser, InaBickle, MarcRizk, SandraGuillen-Boixet, JordinaFranzmann, Titus M.Jahnel, MarcusMarrone, LaraChang, Young-TaeSterneckert, JaredTomancak, PavelHyman, Anthony A.Alberti, Simon
POSTECH Authors
Chang, Young-Tae
Date Issued
May-2018
Publisher
AMER ASSOC ADVANCEMENT SCIENCE
Abstract
Prion-like RNA binding proteins (RBPs) such as TDP43 and FUS are largely soluble in the nucleus but form solid pathological aggregates when mislocalized to the cytoplasm. What keeps these proteins soluble in the nucleus and promotes aggregation in the cytoplasm is still unknown. We report here that RNAcritically regulates the phase behavior of prion-like RBPs. Low RNA/protein ratios promote phase separation into liquid droplets, whereas high ratios prevent droplet formation in vitro. Reduction of nuclear RNA levels or genetic ablation of RNA binding causes excessive phase separation and the formation of cytotoxic solid-like assemblies in cells. We propose that the nucleus is a buffered system in which high RNA concentrations keep RBPs soluble. Changes in RNA levels or RNA binding abilities of RBPs cause aberrant phase transitions.
Prion-like RNA binding proteins (RBPs) such as TDP43 and FUS are largely soluble in the nucleus but form solid pathological aggregates when mislocalized to the cytoplasm. What keeps these proteins soluble in the nucleus and promotes aggregation in the cytoplasm is still unknown. We report here that RNAcritically regulates the phase behavior of prion-like RBPs. Low RNA/protein ratios promote phase separation into liquid droplets, whereas high ratios prevent droplet formation in vitro. Reduction of nuclear RNA levels or genetic ablation of RNA binding causes excessive phase separation and the formation of cytotoxic solid-like assemblies in cells. We propose that the nucleus is a buffered system in which high RNA concentrations keep RBPs soluble. Changes in RNA levels or RNA binding abilities of RBPs cause aberrant phase transitions.
Keywords
AMYOTROPHIC-LATERAL-SCLEROSIS; FUS MUTATIONS; TOXIC GAIN; TDP-43; ALS; TRANSITION; DEGENERATION; MECHANISM; DOMAINS; DISEASE
URI
http://oasis.postech.ac.kr/handle/2014.oak/91958
DOI
10.1126/science.aar7366
ISSN
0036-8075
Article Type
Article
Citation
SCIENCE, vol. 360, no. 6391, page. 918 - 921, 2018-05
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 CHANG, YOUNG TAE
Dept of Chemistry
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