Journal Article

H19 long noncoding RNA controls the mRNA decay promoting function of KSRP

Paola Briata, Andres Ramos, Matteo Giovarelli, Ching-Yi Chen, Roberto Gherzi, Domenico Bordo, Carol J. Wilusz, Margherita Puppo, Gabriele Bucci

2014

Overview

Long noncoding RNAs (lncRNAs) interact with protein factors to regulate different layers of gene expression transcriptionally or posttranscriptionally. Here we report on the functional consequences of the unanticipated interaction of the RNA binding protein K homology-type splicing regulatory protein (KSRP) with the H19 lncRNA (H19). KSRP directly binds to H19 in the cytoplasm of undifferentiated multipotent mesenchymal C2C12 cells, and this interaction favors KSRP-mediated destabilization of labile transcripts such as myogenin. AKT activation induces KSRP dismissal from H19 and, as a consequence, myogenin mRNA is stabilized while KSRP is repurposed to promote maturation of myogenic microRNAs, thus favoring myogenic differentiation. Our data indicate that H19 operates as a molecular scaffold that facilitates effective association of KSRP with myogenin and other labile transcripts, and we propose that H19 works with KSRP to optimize an AKT-regulated posttranscriptional switch that controls myogenic differentiation. Significance Long noncoding RNAs (lncRNAs) provide new layers of complexity to gene expression control. We report on the functional consequences of the interaction between the ssRNA-binding protein K homology-type splicing regulatory protein (KSRP) with H19 lncRNA (H19) in multipotent C2C12 cells able to differentiate in culture toward myotubes in response to activation of cell signaling pathways, including AKT. KSRP and H19 interact exclusively in undifferentiated C2C12 cells, and this favors KSRP’s ability to interact with the promyogenic transcript myogenin and to favor its degradation. AKT activation induces KSRP dissociation from H19 and, as a consequence, from myogenin mRNA that is stabilized. H19 likely acts as a scaffold that favors KSRP-mediated degradation of myogenin to contribute to the maintenance of the undifferentiated state of C2C12 cells.

• Publisher: National Academy of Sciences,National Acad Sciences
• Subject: Animals / Biological Sciences / Cell Line / Cells / Cytoplasm / dissociation / Gene expression / Humans / messenger RNA / myotubes / non-coding RNA / PNAS Plus / Protein Binding / Proteins / regulatory proteins / Ribonucleic acid / RNA / RNA, Long Noncoding - metabolism / RNA, Long Noncoding - physiology / RNA, Messenger - metabolism / RNA-Binding Proteins - metabolism / signal transduction / Trans-Activators - metabolism