How Roquin Family Proteins Control T Cells

The two genetic variants Roquin-1 and Roquin-2 are important components in the activation and differentiation of T cells. The proteins encoded by them are interchangeable in their molecular function, and defects in the Roquin-1 gene can cause ­autoimmune diseases. For the first time, scientists have now analyzed the complex interaction of the two proteins and have examined their activity as regulators of gene expression.

Roquin proteins control the activation and differentiation of T cells by regulating their gene expression at the level of messenger RNA. The function of the RNA-binding proteins is first and foremost to ensure immunological tolerance and to prevent excessive immune reactions – such as in autoimmune diseases.

Katharina Vogel and Stephanie Edelmann of the Institute of Molecular Immunology showed how the two proteins, Roquin-1 and Roquin-2 can replace each other functionally and which consequences result from the combined loss of both Roquin genes. In the case that the Roquin-1san form is present in a single point mutation, Roquin-1 inhibits the function of Roquin-2. In the absence of Roquin-1, Roquin-2 takes over and compensates for its function.

The proteins are consequently interchangeable in their molecular function and fulfill a kind of reserve function for each other. The loss of both Roquin genes leads to an uncontrolled accumulation of effector T cells and particularly of follicular helper T cells. If these T cells then trigger an immune response against the body’s own structures, a clinical picture emerges that is very similar to lupus erythematodes, an autoimmune disease that attacks the skin and internal organs. A single point mutation in the Roquin-1 gene, i.e. the exchange of a single amino acid in the protein, leads to such a disease.

Interestingly, in this case the Roquin-2-protein is unable to take over the function of the defective Roquin-1, resulting in a complete loss of the Roquin function.The research team also identified the molecular targets of the Roquin proteins, the Icos and Ox40 costimulator mRNAs.

This research demonstrates that the Roquin-1 and 2 proteins are of great importance for T cell differentiation in immune reactions. In future studies, the focus will be on elucidating the regulation of these factors because this regulation mechanism can be used as a therapeutic target in the treatment of auto­immune diseases.

Autoimmunity is defined as the inability of an organism to recognize its structural components as endogenous. This leads to a pathological reaction of the immune system against endogenous molecules or tissues which is manifested as an autoimmune disease. The exact causes for the dysregulation are not yet known.

The proteins Roquin-1 and Roquin-2 repress the Icos and Ox40 costimulator mRNAs and regulate the differentiation of T cells. Source: HMGU