Phosphoregulated FMRP Phase Separation Models Activity-dependent Translation Through Bidirectional Control of MRNA Granule Formation

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2019 Feb 16

PMID 30765518

Citations 159

Authors

Brian Tsang

Jason Arsenault

Robert M Vernon

Hong Lin

Nahum Sonenberg

Lu-Yang Wang

Alaji Bah

Julie D Forman-Kay

Affiliations

Soon will be listed here.

Abstract

Activity-dependent translation requires the transport of mRNAs within membraneless protein assemblies known as neuronal granules from the cell body toward synaptic regions. Translation of mRNA is inhibited in these granules during transport but quickly activated in response to neuronal stimuli at the synapse. This raises an important question: how does synaptic activity trigger translation of once-silenced mRNAs? Here, we demonstrate a strong connection between phase separation, the process underlying the formation of many different types of cellular granules, and in vitro inhibition of translation. By using the Fragile X Mental Retardation Protein (FMRP), an abundant neuronal granule component and translational repressor, we show that FMRP phase separates in vitro with RNA into liquid droplets mediated by its C-terminal low-complexity disordered region (i.e., FMRP). FMRP posttranslational modifications by phosphorylation and methylation have opposing effects on in vitro translational regulation, which corroborates well with their critical concentrations for phase separation. Our results, combined with bioinformatics evidence, are supportive of phase separation as a general mechanism controlling activity-dependent translation.

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