Regulation of protein levels in subcellular domains through mRNA transport and localized translation

Abstract

Localized protein synthesis is increasingly recognized as a means for polarized cells to modulate protein levels in subcellular regions and the distal reaches of their cytoplasm. The axonal and dendritic processes of neurons represent functional domains of cytoplasm that can be separated from their cell body by vast distances. This separation provides a biological setting where the cell uses locally synthesized proteins to both autonomously respond to stimuli and to retrogradely signal the cell body of events occurring is this distal environment. Other cell types undoubtedly take advantage of this localized mechanism, but these have not proven as amenable for isolation of functional subcellular domains. Consequently, neurons have provided an appealing experimental platform for study of mRNA transport and localized protein synthesis. Molecular biology approaches have shown both the population of mRNAs that can localize into axons and dendrites and an unexpectedly complex regulation of their transport into these processes. Several lines of evidence point to similar complexities and specificity for regulation of mRNA translation at subcellular sites. Proteomics studies are beginning to provide a comprehensive view of the protein constituents of subcellular domains in neurons and other cell types. However, these have currently fallen short of dissecting temporal regulation of new protein synthesis in subcellular sites and mechanisms used to ferry mRNAs to these sites.

Fig. 1.

Local protein translation in subcellular domains. A, the neuron is comprised of highly specialized subdomains that extend great distances from the cell body. Local protein synthesis within the dendrites plays a critical role in growth and synaptic plasticity. Within the axon, local protein synthesis is involved in growth, mediating the injury response, regeneration, and neuropathic pain and may play a role in plasticity. B, local protein synthesis allows the growth cone to respond autonomously to environmental cues. Attractive turning of the growth cone leads to local translation of mRNAs (blue). In dendrites, translation is activated by transsynaptic stimuli. C, in migrating fibroblasts, mRNAs encoding the microfilament regulating complex actin-related protein 2/3 localize to protrusions at the leading migration edge. Similarly, translation of β-actin in this region contributes to cell polarity and subsequent mobility. D, in epithelial cells, β-actin mRNA is localized to focal adhesions upon integrin binding with the plasma membrane.