Abstract
In neurons, specific mRNAs are transported in a translationally repressed manner along dendrites or axons by transport ribonucleic-protein complexes called RNA granules. ZBP1 is one RNA binding protein present in transport RNPs, where it transports and represses the translation of cotransported mRNAs, including β-actin mRNA. The release of β-actin mRNA from ZBP1 and its subsequent translation depends on the phosphorylation of ZBP1 by Src kinase, but little is known about how this process is regulated. Here we demonstrate that the ribosomal-associated protein RACK1, another substrate of Src, binds the β-actin mRNA/ZBP1 complex on ribosomes and contributes to the release of β-actin mRNA from ZBP1 and to its translation. We identify the Src binding and phosphorylation site Y246 on RACK1 as the critical site for the binding to the β-actin mRNA/ZBP1 complex. Based on these results we propose RACK1 as a ribosomal scaffold protein for specific mRNA-RBP complexes to tightly regulate the translation of specific mRNAs.
Highlights
The localization and translation of mRNAs in specific regions of the cell is an evolutionarily conserved mechanism to regulate the quantity of proteins within specific cellular compartments [1]
We show that Receptor Activated C Kinase 1 (RACK1) represents a docking site on ribosomes for the b-actin mRNA/Zipcode binding protein 1 (ZBP1) complex and that the binding of this complex to RACK1 is critical to the release and translation of b-actin mRNA
Immunofluorescence studies conducted on cultured embryonic cortical neurons confirmed the sub-cellular localization of RACK1 in soma (Fig. 1A) and along dendrites and axons as shown by colocalization with MAP2 and Tau proteins respectively (Figure S1A and S1B) RACK1 appeared in the form of granules in cell body and in neurites (Fig. 1A)
Summary
The localization and translation of mRNAs in specific regions of the cell is an evolutionarily conserved mechanism to regulate the quantity of proteins within specific cellular compartments [1]. The RBPs show a dual function: they act both as mRNA transport factors and as translation repressors At their destinations, neuronal activity stimulates post-translation modifications of RBPs, which promote the release and translation of associated mRNAs. The Zipcode binding protein 1 (ZBP1) is one of several RBPs found in RNPs whose translational regulation has been extensively studied. ZBP1 binds the b-actin mRNA, represses its translation and transports it to growth cones [4]. The phosphorylation of ZBP1 by Src, stimulated by Brain-Derived Neutrophic Factor (BDNF), determines the release and the local translation of b-actin mRNA favoring the growth cone [5,6]
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