RNA-binding protein influences key mediator of cellular inflammation and stress responses

July 31, 2015

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.
-end-
*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

Contact:

Barbara Bachtler
Press Department
Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC)
Robert-Rössle-Straße 10
13125 Berlin
Germany
Phone: +49 (0) 30 94 06 - 38 96
Fax: +49 (0) 30 94 06 - 38 33
e-mail: presse@mdc-berlin.de
https://www.mdc-berlin.de/en

Max Delbrück Center for Molecular Medicine in the Helmholtz Association

Related DNA Articles from Brightsurf:

A new twist on DNA origami
A team* of scientists from ASU and Shanghai Jiao Tong University (SJTU) led by Hao Yan, ASU's Milton Glick Professor in the School of Molecular Sciences, and director of the ASU Biodesign Institute's Center for Molecular Design and Biomimetics, has just announced the creation of a new type of meta-DNA structures that will open up the fields of optoelectronics (including information storage and encryption) as well as synthetic biology.

Solving a DNA mystery
''A watched pot never boils,'' as the saying goes, but that was not the case for UC Santa Barbara researchers watching a ''pot'' of liquids formed from DNA.

Junk DNA might be really, really useful for biocomputing
When you don't understand how things work, it's not unusual to think of them as just plain old junk.

Designing DNA from scratch: Engineering the functions of micrometer-sized DNA droplets
Scientists at Tokyo Institute of Technology (Tokyo Tech) have constructed ''DNA droplets'' comprising designed DNA nanostructures.

Does DNA in the water tell us how many fish are there?
Researchers have developed a new non-invasive method to count individual fish by measuring the concentration of environmental DNA in the water, which could be applied for quantitative monitoring of aquatic ecosystems.

Zigzag DNA
How the cell organizes DNA into tightly packed chromosomes. Nature publication by Delft University of Technology and EMBL Heidelberg.

Scientists now know what DNA's chaperone looks like
Researchers have discovered the structure of the FACT protein -- a mysterious protein central to the functioning of DNA.

DNA is like everything else: it's not what you have, but how you use it
A new paradigm for reading out genetic information in DNA is described by Dr.

A new spin on DNA
For decades, researchers have chased ways to study biological machines.

From face to DNA: New method aims to improve match between DNA sample and face database
Predicting what someone's face looks like based on a DNA sample remains a hard nut to crack for science.

Read More: DNA News and DNA Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.