RC3H1 post-transcriptionally regulates A20 mRNA and modulates the activity of the IKK/NF-κB pathway

Yasuhiro Murakawa, Michael Hinz, Janina Mothes, Anja Schuetz, Michael Uhl, Emanuel Wyler, Tomoharu Yasuda, Guido Mastrobuoni, Caroline C. Friedel, Lars Dölken, Stefan Kempa, Marc Schmidt-Supprian, Nils Blüthgen, Rolf Backofen, Udo Heinemann, Jana Wolf, Claus Scheidereit and Markus Landthaler ()
Additional contact information
Yasuhiro Murakawa: RNA Biology and Posttranscriptional Regulation, Berlin Institute of Medical Systems Biology at the Max-Delbrück Center for Molecular Medicine
Michael Hinz: Signal Transduction in Tumor Cells, Max-Delbrück Center for Molecular Medicine
Janina Mothes: Mathematical Modelling of Cellular Processes, Max-Delbrück Center for Molecular Medicine
Anja Schuetz: Macromolecular Structure and Interaction, Max-Delbrück Center for Molecular Medicine
Michael Uhl: Albert-Ludwigs-Universität Freiburg
Emanuel Wyler: RNA Biology and Posttranscriptional Regulation, Berlin Institute of Medical Systems Biology at the Max-Delbrück Center for Molecular Medicine
Tomoharu Yasuda: Immune Regulation and Cancer, Max-Delbrück Center for Molecular Medicine
Guido Mastrobuoni: Integrative Proteomics and Metabolomics Platform, Berlin Institute of Medical Systems Biology at the Max-Delbrück Center for Molecular
Caroline C. Friedel: Institut für Informatik, Ludwig-Maximilians-Universität
Lars Dölken: Institute for Virology and Immunobiology, University of Würzburg
Stefan Kempa: Integrative Proteomics and Metabolomics Platform, Berlin Institute of Medical Systems Biology at the Max-Delbrück Center for Molecular
Marc Schmidt-Supprian: Technische Universität
Nils Blüthgen: Institute of Pathology, Charité–Universitätsmedizin Berlin, 10117 Berlin, Germany
Rolf Backofen: Albert-Ludwigs-Universität Freiburg
Udo Heinemann: Macromolecular Structure and Interaction, Max-Delbrück Center for Molecular Medicine
Jana Wolf: Mathematical Modelling of Cellular Processes, Max-Delbrück Center for Molecular Medicine
Claus Scheidereit: Signal Transduction in Tumor Cells, Max-Delbrück Center for Molecular Medicine
Markus Landthaler: RNA Biology and Posttranscriptional Regulation, Berlin Institute of Medical Systems Biology at the Max-Delbrück Center for Molecular Medicine

Nature Communications, 2015, vol. 6, issue 1, 1-14

Abstract: Abstract The RNA-binding protein RC3H1 (also known as ROQUIN) promotes TNFα mRNA decay via a 3′UTR constitutive decay element (CDE). Here we applied PAR-CLIP to human RC3H1 to identify ∼3,800 mRNA targets with >16,000 binding sites. A large number of sites are distinct from the consensus CDE and revealed a structure-sequence motif with U-rich sequences embedded in hairpins. RC3H1 binds preferentially short-lived and DNA damage-induced mRNAs, indicating a role of this RNA-binding protein in the post-transcriptional regulation of the DNA damage response. Intriguingly, RC3H1 affects expression of the NF-κB pathway regulators such as IκBα and A20. RC3H1 uses ROQ and Zn-finger domains to contact a binding site in the A20 3′UTR, demonstrating a not yet recognized mode of RC3H1 binding. Knockdown of RC3H1 resulted in increased A20 protein expression, thereby interfering with IκB kinase and NF-κB activities, demonstrating that RC3H1 can modulate the activity of the IKK/NF-κB pathway.

Date: 2015
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DOI: 10.1038/ncomms8367

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