RNA transport and local control of translation

Abstract

In eukaryotes, the entwined pathways of RNA transport and local translational regulation are key determinants in the spatio-temporal articulation of gene expression. One of the main advantages of this mechanism over transcriptional control in the nucleus lies in the fact that it endows local sites with independent decision-making authority, a consideration that is of particular relevance in cells with complex cellular architecture such as neurons. Localized RNAs typically contain codes, expressed within cis-acting elements, that specify subcellular targeting. Such codes are recognized by trans-acting factors, adaptors that mediate translocation along cytoskeletal elements by molecular motors. Most transported mRNAs are assumed translationally dormant while en route. In some cell types, especially in neurons, it is considered crucial that translation remains repressed after arrival at the destination site (e.g., a postsynaptic microdomain) until an appropriate activation signal is received. Several candidate mechanisms have been suggested to participate in the local implementation of translational repression and activation, and such mechanisms may target translation at the level of initiation and/or elongation. Recent data indicate that untranslated RNAs may play important roles in the local control of translation.

Figure 1

Active transport of mRNAs from the nucleus (left, light blue)to peripheral cytoplasmic destination sites in eukaryotic cells. Transport proceeds through a number of sequential phases as follows: (a) Recognition of cis-acting elements by nuclear trans-acting factors (TAFs) (purple ellipses) and formation of ribonucleotide protein (RNP) complexes; (b) nuclear export of RNP particles and recruitment of cytoplasmic TAFs ( yellow ellipses); (c) motor-based active transport of cytoplasmic RNP particles along cytoskeletal filaments (green and blue lines); (d, f ) association with additional cytoplasmic TAFs, such as anchoring proteins, at destination sites (light green ellipses); (e, f ) recruitment of ribosomes and other translational components (not shown) either before (e)or after ( f ) cytoplasmic translocation; ( g) locally controlled translation.

Figure 2

Cap-dependent translation initiation in eukaryotes. Recruitment of the 43S preinitiation complex to the mRNA, mediated by factors of the eIF4 family and poly(A) binding protein (PABP), results in the formation of a 48S complex at the AUG initiator codon. Alternatively to the scenario shown here, eIF4E may remain bound to the cap during scanning (resulting in a looping-out of the 5′ UTR; Jackson 2000); in general, it remains to be established at which point after initial cap-binding the eIF4 factors dissociate from the mRNA and from PABP. Translation may also be initiated in cap-independent fashion, for instance by binding of the 43S complex to an internal ribosome entry site (IRES), which is typically located directly upstream of the AUG start codon (not shown; see Hellen & Sarnow 2001). Some factors (e.g., eIF5) have been omitted for clarity.

Figure 3

Many roads lead to Rome: possible pathways of translational control at the synapse. Translational control can be implemented by activation of various receptor systems (left) and can be mediated at the level of initiation and elongation (right). Mechanisms in addition to those summarized here have been discussed; for example, FMRP has also been reported to repress translation at the level of initiation (Laggerbauer et al. 2001). Green arrows, stimulation; red arrows, inhibition. Aspects of this diagram remain speculative; note that not all factors shown are currently known to be active at the synapse. Factors not drawn to scale.