The microRNA-21-PDCD4 axis prevents type 1 diabetes by blocking pancreatic β cell death

Death of pancreatic beta cells is a pathological hallmark of type 1 diabetes (T1D). However, the molecular mechanisms of beta cell death and its regulation are poorly understood. Here we describe a unique regulatory pathway of beta cell death that comprises microRNA-21, its target tumor suppressor PDCD4, and its upstream transcriptional activator nuclear factor-kappa B (NF-kappa B). In pancreatic beta cells, c-Rel and p65 of the NF-kappa B family activated the mir21 gene promoter and increased miR-21 RNA levels; miR-21 in turn decreased the level of PDCD4, which is able to induce cell death through the Bax family of apoptotic proteins. Consequently, PDCD4 deficiency in pancreatic beta cells renders them resistant to death, and PDCD4 deficiency in NOD or C57BL/6 mice conferred resistance to spontaneous diabetes and diabetes induced by autoimmune T cells or the beta cell toxin streptozotocin (STZ). Thus, the NF-kappa B-microRNA-21-PDCD4 axis plays a crucial role in T1D and represents a unique therapeutic target for treating the disease.