Long non-coding RNA Neat1 is a key translational regulator in hypoxia

Abstract

SUMMARYInternal ribosome entry sites (IRESs) drive translation initiation during stress. In response to hypoxia, (lymph)angiogenic factors responsible for tissue revascularization in ischemic diseases are induced by the IRES-dependent mechanism. Here we searched for IRES trans-acting factors (ITAFs) active in early hypoxia in mouse cardiomyocytes. Using knock-down and proteomics approaches, we show a link between a stressed-induced nuclear body, the paraspeckle, and IRES-dependent translation. Our data reveal that the long non-coding RNA Neat1, an essential paraspeckle component, is a key translational regulator, active on IRESs of (lymph)angiogenic and cardioprotective factor mRNAs. In addition, paraspeckle proteins p54nrb and PSPC1 as well as nucleolin and Rps2, two p54nrb-interacting proteins identified by mass spectrometry, are ITAFs for IRES subgroups. Paraspeckle thus appears as the site of IRESome assembly in the nucleus. Polysome PCR array shows that the Neat1_2 isoform widely affects translation of mRNAs containing IRESs, involved in stress response, angiogenesis or cardioprotection.HighlightsInduction of lncRNA Neat1 and paraspeckle formation correlates with activation of IRES-dependent translation in hypoxic cardiomyocytes.Neat1, an essential paraspeckle component, is the key IRES trans-acting factor (ITAF) of (lymph)angiogenic and cardioprotective factor mRNA IRESs.Paraspeckle proteins p54nrb and PSPC1 as well as nucleolin and Rps2, two p54nrb-interacting proteins, are ITAFs of IRES subgroups.Paraspeckle appears as a platform for IRESome formation in nucleus.The Neat1_2 isoform plays a pivotal role in translation of mRNA containing IRESs and of genes involved in the stress response.GRAPHICAL ABSTRACT