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Immune Biology

Adaptive Immune Response: New Cofactor of Roquin Identified

Roquin has a key role in the adaptive immune response. It controls the activation and differentiation of T cells and thus helps to make the decisions whether or not and which type of immune response will be mounted. Now, a team of scientists of Helmholtz Zentrum München in cooperation with scientists of Ludwig-Maximilians-Universität and the Helmholtz Centre for Environmental Research in Leipzig have identified NUFIP2, a protein with a previously unknown function, as cofactor of Roquin and discovered that NUFIP2 enhances Roquin‘s regulatory function.

© Fotolia/ag visuell

In previous studies, the research group led by Professor Vigo Heissmeyer, head of the Research Unit Molecular Immune Regulation (AMIR) at Helmholtz Zentrum München (HMGU) and professor at Ludwig-Maximilians-Universität (LMU) in cooperation with research groups from the Institute of Structural Biology (HMGU) showed that Roquin binds to the folded regions of the 3' UTR of certain mRNAs with its ROQ domain. This reduces spontaneous activation of T cells and controls differentiation decisions after activation, thereby limiting immune responses to specific reactions and preventing inflammatory reactions in the absence of pathogens. It became now clear that Roquin does not carry out these tasks alone. "We have discovered that Roquin recognizes mRNA and induces degradation together with NUFIP2," said Heissmeyer. "Such cooperative regulation of mRNA transcripts ensures that T cells produce fewer costimulatory receptors and immune responses are attenuated," added Professor Dierk Niessing, research group leader at the STB.

“The NUFIP2 protein, which I have identified in a high-throughput screen, binds directly to Roquin with high affinity, thus altering the Roquin-mediated recognition of target mRNAs. In return, this binding stabilizes NUFIP2 in the cell,“ said Nina Rehage, a former doctoral student at HMGU. “For ICOS and Ox40 in particular, we were able to demonstrate that the complex of NUFIP2 and Roquin reinforces the recognition of unconventional tandem structures in the 3' UTRs. ICOS and Ox40 are costimulatory receptors for T cells and are therefore crucial for the development of specific immune responses. Their regulation is therefore very important,” explained Elena Davydova, PhD student at the STB, and Christine Conrad, PhD student at Ludwig-Maximilians-Universität.

Since T lymphocytes are involved in many diseases, especially autoimmune diseases, allergies and chronic inflammatory reactions, the key to new therapy options lies in the knowledge of the underlying molecular mechanisms. We think that this research contributes to a better understanding of the immune response and may at one point enable new therapies," said Heissmeyer.

A Hela cell line expressing the ICOS receptor was transfected with unspecific siRNAs (grey) or siRNAs against NUFIP2 (red) to selectively repress the biosynthesis of endogenous NUFIP2. The effect of the siRNA knockdown of NUFPI2 on ICOS expression is depicted with flow cytometry. © HMGU/Christine Conrad

Further Information

Original Publication:
Rehage, N. et al. (2018) Binding of NUFIP2 to Roquin promotes recognition and regulation of ICOS mRNA. Nature Communications, DOI: 10.1038/s41467-017-02582-1

The PhD students Nina Rehage and Elena Davydova are members of the Helmholtz Graduate School Environmental Health HELENA.

As German Research Center for Environmental Health, Helmholtz Zentrum München pursues the goal of developing personalized medical approaches for the prevention and therapy of major common diseases such as diabetes mellitus, allergies and lung diseases. To achieve this, it investigates the interaction of genetics, environmental factors and lifestyle. The Helmholtz Zentrum München has about 2,500 staff members and is headquartered in Neuherberg in the north of Munich. Helmholtz Zentrum München is a member of the Helmholtz Association, a community of 19 scientific-technical and medical-biological research centers with a total of about 37,000 staff members. 

The Research Unit Molecular Immunoregulation (AMIR) investigates the molecular mechanisms of physiological and pathological immune responses such as the autoimmune diseases type 1 diabetes and lupus erythematosus. The goal of AMIR is to understand the molecular programs in T cells, which enable the distinction between self and foreign antigenic structures. The focus is on post-transcriptional gene regulation.

The Institute for Structural Biologyinvestigates the spatial structures of biological macromolecules, analyses their structure and dynamics and develops NMR-spectroscopy methods for carrying out these studies. Its goal is to illuminate the structural and molecular mechanisms and their role in disease. The structural data form the basis for the rational design and development of small molecular inhibitors in combination with chemical and biological approaches.

As one of Europe's leading research universities, LMU Munich is committed to the highest international standards of excellence in research and teaching. Building on its 500-year-tradition of scholarship, LMU covers a broad spectrum of disciplines, ranging from the humanities and cultural studies through law, economics and social studies to medicine and the sciences. 15 percent of LMU‘s 50,000 students come from abroad, originating from 130 countries worldwide. The know-how and creativity of LMU's academics form the foundation of the University's outstanding research record. This is also reflected in LMU‘s designation of as a "university of excellence" in the context of the Excellence Initiative, a nationwide competition to promote top-level university research.