Essig, KatharinaKatharinaEssigKronbeck, NinaNinaKronbeckGuimaraes, Joao C.Joao C.GuimaraesLohs, ClaudiaClaudiaLohsSchlundt, AndreasAndreasSchlundtHoffmann, AnneAnneHoffmannBehrens, GesineGesineBehrensBrenner, SvenSvenBrennerKowalska, JoannaJoannaKowalskaLopez-Rodriguez, CristinaCristinaLopez-RodriguezJemielity, JacekJacekJemielityReiche, KristinKristinReicheHoltmann, HelmutHelmutHoltmannHackermüller, JörgJörgHackermüllerSattler, MichaelMichaelSattlerZavolan, MihaelaMihaelaZavolanHeissmeyer, VigoVigoHeissmeyer2022-03-052022-03-052018https://publica.fraunhofer.de/handle/publica/25661510.1038/s41467-018-06184-32-s2.0-85053559831The RNA-binding proteins Roquin-1 and Roquin-2 redundantly control gene expression and cell-fate decisions. Here, we show that Roquin not only interacts with stem-loop structures, but also with a linear sequence element present in about half of its targets. Comprehensive analysis of a minimal response element of the Nfkbid 3'-UTR shows that six stem-loop structures cooperate to exert robust and profound post-transcriptional regulation. Only binding of multiple Roquin proteins to several stem-loops exerts full repression, which redundantly involved deadenylation and decapping, but also translational inhibition. Globally, most Roquin targets are regulated by mRNA decay, whereas a small subset, including the Nfat5 mRNA, with more binding sites in their 3'-UTRs, are also subject to translational inhibition. These findings provide insights into how the robustness and magnitude of Roquin-mediated regulation is encoded in complex cis-elements.en610620journal article