Remote control of gene function by local translation

Abstract

The subcellular position of a protein is a key determinant of its function. Mounting evidence indicates that RNA localization, where specific mRNAs are transported subcellularly and subsequently translated in response to localized signals, is an evolutionarily conserved mechanism to control protein localization. On-site synthesis confers novel signaling properties to a protein and helps to maintain local proteome homeostasis. Local translation plays particularly important roles in distal neuronal compartments, and dysregulated RNA localization and translation cause defects in neuronal wiring and survival. Here, we discuss key findings in this area and possible implications of this adaptable and swift mechanism for spatial control of gene function.

Figure 1

Subcellular RNA Localization in Diverse Cell Types (A) β-actin mRNA localizes to the periphery of migrating fibroblasts (Lawrence and Singer, 1986). (B) β-actin mRNA (magenta, in situ hybridization) localizes to the axonal growth cone of a retinal ganglion cell neuron from a cultured Xenopus laevis eye primordium and partially colocalizes with the dynamic microtubule cytoskeleton (green, anti-tyrosinated tubulin). Superresolution image acquired using a DeltaVision OMX 3D-Structured-Illumination Microscope (Applied Precision), with a 100× 1.4 NA oil objective. Extended focus image from deconvolved Z stack images acquired at 0.125 μm step size B. Lu and C.E.H., unpublished). Scale bar, 5 μm.

Figure 2

Translational Control in Mammals (A) Cap-dependent translation (top). Translation in mammals is mainly regulated at the initiation step. The cap-binding eIF4F complex, downstream of mTORC1, and the 43S preinitiation complex are the major targets of translational control. (B) Regulation of cap-dependent translation (bottom). mTORC1 links cell-intrinsic and -extrinsic signals to translation initiation by phosphorylating S6Ks and 4E-BPs. eIF2α phosphorylation represses translation. Excessively high or low translation activities are associated with neurodevelopmental and neurodegenerative diseases, respectively (see text for more details).

Figure 3

Localized Gene Expression by Translational Control of Localized mRNAs mRNAs and RNA-binding proteins form heterogeneous mRNP granules, which are transported to subcellular compartments in a translationally repressed state. Of locally stored mRNAs (local transcriptome), a selected pool of mRNAs is translated (local translatome) depending on the signaling input.