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

Abstract

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. Among small noncoding RNAs, microRNAs (miRNAs) repress gene expression by inhibiting translation and/or promoting decay of target mRNAs (1), with RBPs being able to control miRNA maturation from precursors or influence miRNA function (1, 2). A new class of transcripts referred to as long noncoding RNAs (lncRNAs, arbitrarily defined as longer than 200 nt) has recently moved to the forefront of regulatory RNA research (3). lncRNAs had been originally considered epigenetic regulators of gene expression, but the emphasis placed on the ways they regulate chromatin state likely obscures the full repertoire of their functions (4-6). Other roles of lncRNAs include posttranscriptional regulation, posttranslational control of protein activity, organization of protein complexes, as well as cell-cell signaling (4, 6). lncRNAs have been implicated in cellular events as different as cell cycle regulation, pluripotency, apoptosis, and DNA damage response, to name just a few (5, 6). Not surprisingly, lncRNA expression is altered in cancer, and it is becoming clear that some lncRNAs can control cell transformation by regulating vital cellular functions (7). Nevertheless, the composition and function of ribonucleoprotein complexes, including lncRNAs, is generally uncharacterized.Studies performed in primary and cultured cells as well as in mice proved that the K homology (KH)-type splicing regulatory protein (KSRP), a single-stranded RBP that interacts with nucleic acids through four hnRNP KH domains, is able to integrate different levels of gene expression and is required for proper immune response, lipid metabolism, cell fate decisions, and tissue regeneration (see ref. 8 for a recent review). We and others have found that KSRP negatively regulates gene expression via at least two distinct and integrated posttranscriptional mechanisms: (i) by promoting decay of unstable mRNAs [mainly targeting AU-rich elements (AREs) in their 3′UTRs] (8, 9) and (ii) by favoring maturation of select miRNAs from precursors (8, 10). Brie...

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