Molecular characterization of the type 2 diabetes-associated interleukin-6 receptor single nucleotide polymorphism p.V385I (rs2228146).

The cytokine Interleukin-6 (IL-6) activates its target cells through the membrane-bound IL-6 receptor (IL-6R). IL-6 crucially controls important metabolic functions of the human body. Low-grade inflammation, including increased IL-6 serum levels, contribute to the development of autoimmune diseases like type 2 diabetes (T2D). In this study, we have analyzed the single nucleotide polymorphism of the IL-6R rs2228146 that is associated with T2D and results in the exchange of a single amino-acid residue within the IL-6R protein (p.V385I). We show that the affected amino-acid residue is located within the transmembrane helix of the IL-6R. The IL-6R-V385I variant matures properly and is transported to the cell surface in comparable amounts as the IL-6R-WT, which is clearly distinct from the established IL-6R SNP rs2228145. We further show that IL-6R-V385I can be cleaved by the metalloproteases ADAM10 and ADAM17, generating a soluble IL-6R, and that the membrane-bound form can perform IL-6 classic signaling.