PICK1 links Argonaute 2 to endosomes in neuronal dendrites and regulates miRNA activity

MicroRNAs fine-tune gene expression by inhibiting the translation of mRNA targets. Argonaute (Ago) proteins are critical mediators of microRNA-induced post-transcriptional silencing and have been shown to associate with endosomal compartments, but the molecular mechanisms that underlie this process are unclear, especially in neurons. Here, we report a novel interaction between Ago2 and the BAR-domain protein, PICK1. We show that PICK1 promotes Ago2 localization at endosomal compartments in neuronal dendrites and inhibits Ago2 function in translational repression following neuronal stimulation. We propose that PICK1 provides a link between activity- dependent endosomal trafficking and local regulation of translation in neurons. Synopsis image The BAR- and PDZ-domain protein PICK1 is shown to interact with and inhibit Ago2, the catalytic component of the RISC, on endosomes. Specific neuronal stimulation reduces the interaction resulting in enhanced Ago2-dependent gene silencing. PICK1 promotes endosomal association of Ago2 and inhibits its function. cLTD induction causes PICK1 and Ago2 to dissociate and leads to enhanced miRNA-mediated gene silencing.