Messenger (mRNA) molecules are a key component of protein biosynthesis. They are first transcribed as a “working copy” of the DNA and then translated into protein molecules. RNA-binding proteins such as RC3H1 (also known as ROQUIN) regulate the degradation of the mRNA molecules and thus prevent the production of specific proteins. Researchers at the Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC) have now shown that ROQUIN binds several thousand mRNA molecules. They demonstrated that ROQUIN also influences the gene regulator NF-kappaB, a key mediator of cellular inflammation and stress responses (Nature Communications, Article number: 7367)*.
RC3H1/ROQUIN has already been described in previous studies as an RNA-binding protein that influences the stability of various mRNAs. Until now, however, it was unclear how ROQUIN recognizes mRNAs and how many mRNAs are regulated by ROQUIN. Dr. Yasuhiro Murakawa and Dr. Markus Landthaler of the Berlin Institute for Medical Systems Biology (BIMSB) of the MDC, in collaboration with the MDC research groups led by Professor Udo Heinemann, Dr. Stefan Kempa, Professor Claus Scheidereit, Dr. Jana Wolf and others, showed that ROQUIN binds to more than 3,800 different mRNAs, and they identified more than 16,000 sites to which the protein binds.
Thus, ROQUIN appears to have greater influence on the regulation of gene expression than previously thought. In addition, the researchers identified the RNA recognition sequences of ROQUIN, thus providing insight into where protein-RNA interactions take place.
ROQUIN regulates the response to DNA damage
ROQUIN preferentially binds mRNAs generated in response to DNA damage but also in the context of inflammatory responses. Many of the affected mRNAs encode for proteins, which in turn influence the activity of genes and thus regulate the production of other proteins. According to the researchers, ROQUIN contributes to the fine-tuning of the regulatory mechanisms.
One of the target transcripts of ROQUIN is the mRNA coding for the protein A20 (also known as TNFAIP3). A20 serves as feedback control of the IkappaBalpha-kinase complex (IKK) that regulates the activation of the gene regulator NF-kappaB. The IKK/NF-kappaB pathway regulates the expression of a number of genes and is one of the key mediators in inflammatory and cellular stress responses, e.g. induced by DNA damage.
To prevent the sustained activation of the IKK/NF-kappaB pathway, this signaling pathway itself induces the increased expression of proteins such as A20, accompanied by decreased IKK/NF-kappaB activation. By regulating the decay of the mRNA for A20, ROQUIN thus indirectly modulates the activity of the IKK/NF-kappaB pathway.
Better understanding of autoimmune diseases
The researchers hypothesize that ROQUIN may play an even more extensive functional role and is involved in other signaling pathways, where it shortens the life span of protein-encoding mRNAs and thus enables fine-tuning. These findings are important to better understand and possibly prevent autoimmune diseases. The protein A20, for example, is known as a protective factor against arthritis. Knockdown of ROQUIN, which results in increased A20 protein expression, may therefore represent an approach to treating this chronic joint inflammation disease.
*RC3H1 post-transcriptionally regulates A20 mRNA and modulates the activity of the IKK/NF-kB pathway
Yasuhiro Murakawa1, Michael Hinz2, Janina Mothes3, Anja Schuetz4,5, Michael Uhl6, Emanuel Wyler1, Tomoharu Yasuda7, Guido Mastrobuoni8, Caroline C. Friedel9, Lars Dölken10, Stefan Kempa8, Marc Schmidt-Supprian11, Nils Blüthgen12,13, Rolf Backofen6, Udo Heinemann4,14, Jana Wolf3, Claus Scheidereit2 & Markus Landthaler1
1 RNA Biology and Posttranscriptional Regulation, Berlin Institute of Medical Systems Biology at the Max-Delbrück Center for Molecular Medicine, 13125 Berlin, Germany.
2 Signal Transduction in Tumor Cells, Max-Delbrück Center for Molecular Medicine, 13125 Berlin, Germany.
3 Mathematical Modelling of Cellular Processes, Max-Delbrück Center for Molecular Medicine, 13125 Berlin, Germany.
4 Macromolecular Structure and Interaction, Max 97078-Delbrück Center for Molecular Medicine, 13125 Berlin, Germany.
5 Helmholtz Protein Sample Production Facility, Max Delbrück Center for Molecular Medicine, 13125 Berlin, Germany.
6 Department of Computer Science and Centre for Biological Signalling Studies (BIOSS), Albert-Ludwigs-Universität Freiburg, 79110 Freiburg, Germany.
7 Immune Regulation and Cancer, Max-Delbrück Center for Molecular Medicine, 13125 Berlin, Germany.
8 Integrative Proteomics and Metabolomics Platform, Berlin Institute of Medical Systems Biology at the MaxDelbrück Center for Molecular, 13125 Berlin, Germany.
9 Institut für Informatik, Ludwig-Maximilians-Universität, 80333 München, Germany.
10 Institute for Virology and Immunobiology, University of Würzburg, 97078 Würzburg, Germany.
11 Department of Hematology and Oncology, Technische Universität, 81675 München, Germany.
12 Institute of Pathology, Charité–Universitätsmedizin Berlin, 10117 Berlin, Germany.
13 Integrative Research Institute (IRI) for the Life Sciences and Institute for Theoretical Biology, Humboldt-Universität zu Berlin, 10115 Berlin, Germany.
14 Chemistry and Biochemistry Institute, Freie Universität Berlin, 14195
Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC)
Phone: +49 (0) 30 94 06 - 38 96
Fax: +49 (0) 30 94 06 - 38 33
Barbara Bachtler | Max-Delbrück-Centrum für Molekulare Medizin in der Helmholtz-Gemeinschaft
Researchers identify potentially druggable mutant p53 proteins that promote cancer growth
09.12.2016 | Cold Spring Harbor Laboratory
Plant-based substance boosts eyelash growth
09.12.2016 | Fraunhofer-Institut für Angewandte Polymerforschung IAP
Physicists of the University of Würzburg have made an astonishing discovery in a specific type of topological insulators. The effect is due to the structure of the materials used. The researchers have now published their work in the journal Science.
Topological insulators are currently the hot topic in physics according to the newspaper Neue Zürcher Zeitung. Only a few weeks ago, their importance was...
In recent years, lasers with ultrashort pulses (USP) down to the femtosecond range have become established on an industrial scale. They could advance some applications with the much-lauded “cold ablation” – if that meant they would then achieve more throughput. A new generation of process engineering that will address this issue in particular will be discussed at the “4th UKP Workshop – Ultrafast Laser Technology” in April 2017.
Even back in the 1990s, scientists were comparing materials processing with nanosecond, picosecond and femtosesecond pulses. The result was surprising:...
Have you ever wondered how you see the world? Vision is about photons of light, which are packets of energy, interacting with the atoms or molecules in what...
A multi-institutional research collaboration has created a novel approach for fabricating three-dimensional micro-optics through the shape-defined formation of porous silicon (PSi), with broad impacts in integrated optoelectronics, imaging, and photovoltaics.
Working with colleagues at Stanford and The Dow Chemical Company, researchers at the University of Illinois at Urbana-Champaign fabricated 3-D birefringent...
In experiments with magnetic atoms conducted at extremely low temperatures, scientists have demonstrated a unique phase of matter: The atoms form a new type of quantum liquid or quantum droplet state. These so called quantum droplets may preserve their form in absence of external confinement because of quantum effects. The joint team of experimental physicists from Innsbruck and theoretical physicists from Hannover report on their findings in the journal Physical Review X.
“Our Quantum droplets are in the gas phase but they still drop like a rock,” explains experimental physicist Francesca Ferlaino when talking about the...
16.11.2016 | Event News
01.11.2016 | Event News
14.10.2016 | Event News
09.12.2016 | Life Sciences
09.12.2016 | Ecology, The Environment and Conservation
09.12.2016 | Health and Medicine