The dialogue between the beta-cell and the immune system in type 1 diabetes: role of glucose-regulated protein 78 in human beta-cells

Type 1 diabetes is an autoimmune disease characterized by infiltration of islets of Langerhans by immune cells, which release pro-inflammatory cytokines causing beta-cell death, and eventually insulin deficiency. Cytokine-induced beta-cell death is mediated, at least partially, by endoplasmic reticulum (ER) stress, with a central role for glucose-regulated protein 78 (GRP78). GRP78 is mainly known for its chaperone function in the ER, however, several studies in different models have demonstrated its role as a multifunctional receptor at the plasma membrane. Our laboratory has gathered important results to accept that GRP78 is post-translationally modified by citrullination upon exposure of beta-cells to inflammation, is transported to the beta-cell membrane and is secreted in the surroundings of the beta-cells, obtained in rodent cell lines and mouse models.

The goal of the present project is to investigate the role of GRP78, especially citrullinated GRP78, in the destruction of human beta-cells in the context of type 1 diabetes. More specifically, we want to elucidate how GRP78 moves to the beta-cell surface and is secreted by stressed beta-cells, where the citrullination is happening and what the role of membrane GRP78 is in the dialogue between the beta-cell and the immune system. Finally, we wish explore whether citrullinated GRP78 behaves as an autoantigen in human type 1 diabetic patients and whether new biomarkers can be derived from this observation.