Subcellular communication through RNA transport and localized protein synthesis

Abstract

Interest in the mechanisms of subcellular localization of mRNAs and the effects of localized translation has increased over the last decade. Polarized eukaryotic cells transport mRNA-protein complexes to subcellular sites, where translation of the mRNAs can be regulated by physiological stimuli. The long distances separating distal neuronal processes from their cell body have made neurons a useful model system for dissecting mechanisms of mRNA trafficking. Both the dendritic and axonal processes of neurons have been shown to have protein synthetic capacity and the diversity of mRNAs discovered in these processes continues to increase. Localized translation of mRNAs requires a co-ordinated effort by the cell body to target both mRNAs and necessary translational machinery into distal sites, as well as temporal control of individual mRNA translation. In addition to altering protein composition locally at the site of translation, some of the proteins generated in injured nerves retrogradely signal to the cell body, providing both temporal and spatial information on events occurring at distant subcellular sites.

Figure 1. Spatial signaling of nerve injury through localized mRNA translation

The schematic illustrates a segment of distal axon from proximal (left) to distal (right]. Injury to the axon causes an increase in axoplasmic [Ca²⁺] from influx and release of intracellular stores [1]. This triggers translation of axonal mRNAs including Importin β1, RanBP1, and vimentin [3]. The newly synthesized RanBP1 causes dissociation of the Importin α complex that includes Ran-GAP [2,4]. Importin α is then able to heterodimerize with newly synthsized Importin β1 [5]. Ca²⁺-triggered protease activity cleaves the newly synthesized Vimentin protein [6], generating a scaffold to link injury-activated Erks to the Importin α/β1 complex for retrograde transport to the cell body through the dynein motor proteins [7].

Figure 2. Sequential assembly of transport RNPs through mRNA-protein interactions

β-actin mRNA targeting is used as an example here to illustrate sequential assembly of RNA transport granule or RNPs. The KHSRP protein, ZBP2, initially binds to nascent β-actin transcript in the nucleus [2]. This facilitates binding of ZBP1 in the nucleus [3], with the ZBP1-β-actin complex eventually localizing into distal cytoplasmic sites through interaction with microtubule motor proteins in the cytoplasm [6]. This interaction is presumably as part of a large RNP complex with additional protein linking ZBP1-β-actin to the plus-ended kinesin motor protein, but also sequester the mRNA(s) from translational machinery [4 & 5]. By definition, ZBP1 can shuttle between the cytoplasm and nucleus [1]; however it is not clear whether ZBP1 is recycled from distal cytoplasmic processes back to the nucleus.