Nedd4 family interacting protein 1 (Ndfip1) promotes death of pancreatic beta cells

High-throughput siRNA screening was employed to identify novel genes that regulate cytokine-induced death of pancreatic β-cells. One of the 'hits' was NEDD4 family interacting protein 1 (Ndfip1), an adaptor and activator of Nedd4-family ubiquitin ligases. Silencing of Ndfip1 inhibited cytokine-induced Apoptosis of mouse and human pancreatic islets and promoted glucose-stimulated Insulin secretion. These effects were associated with an increase in the cellular content of JunB, a potent inhibitor of ER stress and Apoptosis. Silencing of Ndfip1 also increased the expression of ATF4, IRE-1α, and the spliced form of XBP that govern the unfolded protein response (UPR) and relieve cytokine-induced ER stress, while overexpression of Ndfip1 exerted opposite effects. These findings implicate Ndfip1 in the degradation of JunB; inhibition of the UPR and Insulin secretion; and promotion of cytokine-induced death of pancreatic β-cells.