Long non-coding RNA Neat1 and paraspeckle components are translational regulators in hypoxia
Anne-Claire Godet, Émilie Roussel, Florian David, Fransky Hantelys, Florent Morfoisse, Joffrey Alves, Françoise Pujol, Isabelle Ader, Édouard Bertrand, Odile Burlet‐Schiltz, Carine Froment, Anthony K. Henras, Patrice Vitali, Éric Lacazette, Florence Tatin, Barbara Garmy‐Susini, Anne‐Catherine Prats
Abstract
Internal 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. Furthermore, smiFISH experiments demonstrate the recruitment of IRES-containing mRNA into paraspeckle during hypoxia. 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 p54 nrb and PSPC1 as well as nucleolin and RPS2, two p54 nrb -interacting proteins identified by mass spectrometry, are ITAFs for IRES subgroups. Paraspeckle thus appears as a platform to recruit IRES-containing mRNAs and possibly host IRESome assembly. Polysome PCR array shows that Neat1 isoforms regulate IRES-dependent translation and, more widely, translation of mRNAs involved in stress response.