Translation and silencing in RNA granules: a tale of sand grains

Abstract

The transcriptome at the synapse consists of thousands of messengers encoding several cellular functions, including a significant number of receptors and ion channels and associated proteins. The concerted translational regulation of all these molecules contributes to the dynamic control of synaptic strength. Cumulative evidence supports that dendritic RNA granules and mRNA-silencing foci play an important role in translational regulation. Several relevant RBPs - FMRP; FUS/TLS; TDP-43; Staufen; Smaug; Pumilio; CPEB; HuD; ZBP1; and DDX6 among others - form granules that contain dormant mRNAs repressed by multiple pathways. Recent reports indicate that dendritic granules may contain stalled polysomes, and furthermore, active translation may occur in association with RNA granules. Here, we discuss the molecules and pathways involved in this continuum of RNA granules that contain masked mRNAs, mRNAs trapped in inactive polysomes or mRNAs engaged in translation.

Keywords: RNA granule; localized translation; mRNA silencing foci; polysome stalling; processing bodies; synapse plasticity.

FIGURE 1

A continuum between mRNA silencing foci and translationally active granules. Transcripts are repressed in large complexes containing specific RBPs, termed mRNA silencing foci. Among other proteins, FMRP, FUS/TLS, ZBP1, and Smaug1/Samd4a form different masking granules. For simplicity, these regulatory factors are depicted together in the same granule. These mRNA-silencing foci respond to synaptic activity and reversibly release mRNAs to allow their translation (black arrows). Speculatively, granule reorganization and release of factors may allow translation at their periphery (dotted arrows). Granules with stalled polysomes are found in dendritic granules and may contain FMRP and Staufen molecules. A role for DDX6/RCK/p54/Me31B, which is present in dendritic granules and stalls polysomes in yeast, is speculated (see the text). DDX6/RCK/p54/Me31B would be recruited through the interaction with FMRP and additional RBPs. Dissolution or restructuration of the granules to release stalling factors would allow translation in either free polysomes or granule-associated polysomes (dotted arrows). Granule-associated translation was demonstrated for ARC/Arg3.1 mRNA and FMRP mRNA and might be a common mechanism that also operates in dendritic PBs. The role of FUS/TLS is speculated from data from non-neuronal cells. Translation would occur in the granule periphery, and this may involve reorganization of the mRNA-silencing foci or stalled polysome granules.