Protein Kinase KIS Localizes to RNA Granules and Enhances Local Translation

Abstract

The regulation of mRNA transport is a fundamental process for cytoplasmic sorting of transcripts and spatially controlled translational derepression once properly localized. There is growing evidence that translation is locally modulated as a result of specific synaptic inputs. However, the underlying molecular mechanisms that regulate this translational process are just emerging. We show that KIS, a serine/threonine kinase functionally related to microtubule dynamics and axon development, interacts with three proteins found in RNA granules: KIF3A, NonO, and eEF1A. KIS localizes to RNA granules and colocalizes with the KIF3A kinesin and the ␤-actin mRNA in cultured cortical neurons. In addition, KIS is found associated with KIF3A and 10 RNP-transported mRNAs in brain extracts. The results of knockdown experiments indicate that KIS is required for normal neurite outgrowth. More important, the kinase activity of KIS stimulates 3 untranslated region-dependent local translation in neuritic projections. We propose that KIS is a component of the molecular device that modulates translation in RNA-transporting granules as a result of local signals.There are two important reasons why proteins are localized through their mRNAs rather than directly. First, mRNA localization not only targets the protein to the correct region of the cell but also prevents its expression elsewhere. The second reason for localizing a protein through its mRNA is that it devolves the control of protein expression to individual regions of the cytoplasm. This allows a cell to respond rapidly to a local requirement for the protein and makes it possible to regulate gene expression independently in different subcompartments of the cell (21, 32, 37). These factors are particularly important in large and highly polarized cells, such as neurons, where translation of localized mRNAs in growth cones seems to be important for axon guidance, whereas local control of protein synthesis in dendrites contributes to synaptic plasticity (6, 36). Localized mRNAs are usually transported in large ribonucleoprotein particles (RNPs), which have been referred to as RNA granules. It is thought that this structure serves to prevent premature mRNA translation/degradation during transport and that mRNAs might be released into a translationally competent form by locally originated signals (23, 33). RNPs vary in composition and include multiple mRNAs, ribosomes, and regulatory proteins, as well as molecular-motor proteins (2). Two studies using different approaches have attempted a molecular characterization of RNPs isolated from neural tissue. The first study used kinesin KIF5A in an affinity purification approach and identified a large number of proteins in granules from the adult mouse brain, including known regulators of mRNA transport (Pur␣ and Staufen1) and eukaryotic translation factors (eIF2A and eEF1A), as well as CaMKII␣ and Arc mRNAs (19). The second study (9) isolated a fraction enriched in RNPs from embryonic rat brains and demonstrated the presence of the ␤-act...

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“…Nevertheless, suggestively significant associations were identified in a region containing UHMK1, a gene that encodes the brain-enriched protein kinase KIS. Animal models suggest that UHMK1 is highly expressed in the brain, and knockdown of this gene effects the development of cortical neurons in culture [37]. In line with our findings, UHMK1 knockout mice display a distinct deficit in fear conditioning, which is accompanied by downregulation of genes implicated in the aetiology of anxiety and fear, including multiple components of GABA A receptors [38].…”

A Comparative Quantitative Assessment of Axonal and Dendritic mRNA Transport in Maturing Hippocampal Neurons

“…However, cell biological and biochemical studies have identified RNA granule association with KIF5 (kinesin-1) and KIF3 (kinesin-2) in dendrites, KIF3C in axons, and kinesin-1 and dynein in Drosophila S2 cells [33], [34], [35], [36], [37]. A role for microtubule-dependent motor proteins in transporting mRNA is also consistent with reductions in mRNA localization within neurites following microtubule destabilization with colchicine [26], [38].…”

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