IP6K1 upregulates the formation of processing bodies by promoting proteome remodeling on the mRNA cap

Abstract

Inositol hexakisphosphate kinases (IP6Ks) are ubiquitously expressed small molecule kinases that catalyze the conversion of the inositol phosphate IP6 to 5-IP7. IP6Ks have been reported to influence cellular functions by protein-protein interactions independent of their enzymatic activity. Here, we show that IP6K1 regulates the formation of processing bodies (P-bodies), which are cytoplasmic ribonucleoprotein granules that serve as sites for storage of translationally repressed mRNA. Cells with reduced levels of IP6K1 display a dramatic reduction in the number of P-bodies, which can be restored by the expression of active or catalytically inactive IP6K1. IP6K1 does not localize to P-bodies, but instead facilitates the formation of P-bodies by promoting translation suppression. We demonstrate that IP6K1 is present on ribosomes, where it interacts with proteins that constitute the mRNA decapping complex - the scaffold protein EDC4, activator proteins DCP1A/B, and the decapping enzyme DCP2. IP6K1 also interacts with components of the eIF4F translation initiation complex - the scaffolding protein eIF4G1, the RNA helicase eIF4A2, and the cap binding protein eIF4E. The RNA helicase DDX6 and the eIF4E binding protein 4E-T are known to promote translation suppression to facilitate P-body formation. We show that IP6K1 binds to DDX6 and promotes the interaction of DDX6 and 4E-T with the cap binding protein eIF4E, and also enhances the binding between DDX6 and EDC4, thus acting to suppress mRNA translation and promote mRNA decapping. Our findings unveil IP6K1 as a novel facilitator of proteome remodelling on the mRNA cap, tipping the balance in favour of translation repression over initiation, and thus leading to the formation of P-bodies.