Phosphoregulated FMRP phase separation models activity-dependent translation through bidirectional control of mRNA granule formation
- Proc Natl Acad Sci U S A. 2019 Mar 5;116(10):4218-4227. doi: 10.1073/pnas.1814385116.
- 1. Program in Molecular Medicine, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada.
- 2. Department of Biochemistry, University of Toronto, Toronto, ON M5S 1A8, Canada.
- 3. Program in Neuroscience & Mental Health, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada.
- 4. Department of Physiology, University of Toronto, Toronto, ON M5S 1A8, Canada.
- 5. Department of Biochemistry, McGill University, Montreal, QC H3G 1Y6, Canada; [email protected] [email protected] [email protected].
- 6. Goodman Cancer Research Centre, McGill University, Montreal, QC H3A 1A3, Canada.
- 7. Program in Molecular Medicine, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; [email protected] [email protected] [email protected].
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., FMRPLCR). FMRPLCR 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.