PICK 1 links Argonaute 2 to endosomes in neuronal dendrites and regulates mi RNA activity

Abstract

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.

NMDAR ‐dependent Argonaute 2 phosphorylation regulates mi RNA activity and dendritic spine plasticity

“…We analysed two dendritically regulated UTRs; LIMK1 , which is regulated by miR‐134 (Schratt et al , 2006), and APT1 , which is regulated by miR‐138 (Siegel et al , 2009). Both of these miRNAs have been shown previously to regulate dendritic spine morphology (Schratt et al , 2006; Siegel et al , 2009), and we previously demonstrated that NMDAR activation increased translational repression of the LIMK1 reporter via miR‐134 and of the APT1 reporter via miR‐138 within 10 min after stimulation (Antoniou et al , 2014; Rajgor et al , 2017). Knockdown of Ago2 by shRNA caused a dramatic increase in expression of both reporter constructs, consistent with a deficit of miRNA‐mediated translational repression, and NMDAR stimulation had no effect under these conditions (Fig 5A and B).…”

“…While the interaction between Ago2 and MOV10 was unaffected by S387 mutations, association with DDX6 showed a similar pattern as GW182 binding (Fig 3A). We previously described an interaction between Ago2 and the BAR domain protein PICK1, which dissociates in response to NMDAR stimulation (Antoniou et al , 2014; Rajgor et al , 2017). This interaction was unaffected by S387 mutations in Ago2 (Fig 3A).…”

Intracellular and extracellular microRNA: An update on localization and biological role

“…Apart from the ER, cellular endosomes might be involved in the process of RNA silencing: AGO2 has been found in both recycling endosomes (Antoniou et al, 2014) and multivesicular bodies (MVB) (Gibbings et al, 2009). MVBs are formed by the invaginations of endosomes and subsequent formation of so-called intraluminal vesicles (ILV) (reviewed in (Kowal et al, 2014)).…”

RISC assembly: Coordination between small RNAs and Argonaute proteins

“…In flies and humans, AGO subfamily proteins are reported to localize at non-membranous bodies such as P-bodies and/or membranous organelles such as endoplasmic reticulum (ER), multivesicular bodies (MVBs) and Golgi [161][162][163][164][165][166][167][168][169][170][171][172][173][174][175][176][177][178][179][180].…”