Autoimmune mechanism: NMR and X-ray clues

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  • Published: Aug 1, 2014
  • Author: David Bradley
  • Channels: NMR Knowledge Base
thumbnail image: Autoimmune mechanism: NMR and X-ray clues

Self aware

Roquin (blue) binding to mRNA (violet). Credit: Sattler/HMGU

NMR spectroscopists, X-ray crystallographers and their colleagues have taken an important step closer to understanding the molecular mechanism behind autoimmune diseases. They have solved the three-dimensional structure of the Roquin protein when it is bound to messenger RNA. The results revealed that there is a much wider range of functionally important Roquin binding partners than previously assumed. Researchers at the Helmholtz Zentrum München, the Ludwig-Maximilians University of Munich (LMU) and the Technische Universität München (TUM) in Germany report details of their findings in the journal Nature Structural & Molecular Biology.

Autoimmune disorders occur when a trigger stimulates the immune system into action against healthy body tissues and treats them as if they are pathogens or other foreign particle. The tissue becomes inflamed, painful and ultimately destroyed. Type 1 diabetes in which the insulin-producing cells in the pancreas are damaged is an example of an autoimmune disease. In the case of systemic lupus erythematosus, almost any part of the body can be attacked by the immune system. Other important examples include celiac disease, sarcoidosis, Sjögren's syndrome, Churg-Strauss Syndrome, Hashimoto's thyroiditis, Graves' disease, idiopathic thrombocytopenic purpura, Addison's disease, rheumatoid arthritis, polymyositis and dermatomyositis. It is estimated that between five and ten percent of the population suffers an autoimmune disease.

Roquin on

The Roquin protein, discovered in 2005, controls T-cell activation and differentiation by regulating the expression of certain messenger ribonucleic acids (mRNAs). When it functions correctly, it damps down the immune response preventing "self" being attacked. Genetic predisposition and numerous complex environmental factors can give rise to an autoimmune disorder. However, it is only in rare cases that a single gene is to blame. However, just one mutation in the Roquin gene in a mouse model is known to give ruse to lupus. The same mutation also increases the susceptibility to Type 1 diabetes, rheumatoid arthritis and induced angioimmunoblastic T-cell lymphoma.

The interdisciplinary team composed of research groups led by Michael Sattler, Dierk Niessing and Vigo Heissmeyer at Helmholtz, LMU and TUM, respectively, have now gained an unprecedented insight into how Roquin recognizes its RNA binding partner and thereby controls T-cell functions using X-ray diffraction at Helmholtz . The XRD study gave them the spatial structure of the RNA-binding domain of Roquin when its target is bound. Meanwhile, the interaction of Roquin with additional RNA binding partners was studied in solution using NMR spectroscopy at the Bavarian NMR Center, a joint research infrastructure of Helmholtz and TUM.

Redacting regulations

The combination of these studies allowed the team to confirm the biological significance of the molecular recognition of the RNA by studying Roquin-dependent gene regulation in cellular systems.

"To our surprise, these results indicate that a greater range of binding modes plays an important functional role for the gene regulation in T-cells," Sattler explains. The findings suggest that Roquin regulates a larger number of genes than was previously assumed. In addition to the mRNAs with optimal recognition motifs, which are tightly bound and predominantly regulated by Roquin, there is a potentially much larger number of mRNAs which are more weakly bound, but nevertheless regulated by Roquin. "On the basis of these findings we will now focus on understanding how Roquin levels are regulated in T-cells, since strong and weakly bound target mRNAs will experience a principally different regulation when the availability of the protein varies," adds Heissmeyer.

Understanding the way in which Roquin and RNA interact could be a prerequisite for controlling the function of Roquin and using its role for therapeutic strategies to modulate the harmful effects of autoimmune diseases on the body. With this in mind, the team is now planning follow-up studies. Indeed, "The next steps are looking at other CDEs and understanding the molecular mechanisms of Roquin," Sattler told SpectroscopyNOW.

Related Links

Nature Struct Biol, 2014, online: "Structural basis for RNA recognition in roquin-mediated post-transcriptional gene regulation"

Article by David Bradley

The views represented in this article are solely those of the author and do not necessarily represent those of John Wiley and Sons, Ltd.

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