NrCAM activates the NF-κB signalling pathway by competitively binding to SUMO-1 and promotes Th17 cell differentiation in Graves' disease.

This study aimed to explore the molecular mechanism of neuronal cell adhesion molecule (NrCAM) by regulating Th17 cell differentiation in the pathogenesis of Graves' disease (GD). Naïve CD4⁺ T cells were isolated from peripheral blood mononuclear cells of GD patients and healthy control (HC) subjects. During the differentiation of CD4⁺ T cells into Th17 cells, NrCAM level in GD group was improved. Interference with NrCAM in CD4⁺ T cells of GD patients decreased the percentage of Th17 cells. NrCAM overexpression in CD4⁺ T cells of HC subjects increased the percentage of Th17 cells and upregulated p-IκBα, p50, p65, c-Rel protein expressions, and NF-κB inhibitor BAY11-7082 partially reversed NrCAM effect. NrCAM overexpression promoted the degradation of IκBα, and overexpression of small ubiquitin-related modifier 1 (SUMO-1) inhibited IκBα degradation. NrCAM overexpression reduced IκBα binding to SUMO-1. During Th17 cell differentiation in HC group, NrCAM overexpression increased IL-21 levels and secretion, and IL-21 neutralizing antibody reversed this effect. IL-21 level was decreased after p65 interference in CD4⁺ T cells of HC subjects. p65 interacts with IL-21 promoter region. In conclusion, NrCAM binds to SUMO-1 and increases phosphorylation of IκBα, leading to activation of NF-κB pathway, which promotes Th17 cell differentiation.