Abstract
Type 1 diabetes is a chronic autoimmune disease characterized by specific destruction of pancreatic β-cells by the immune system. Linkage and genome-wide association studies have identified more than 50 loci across the human genome associated with risk of type 1 diabetes. Recently, basic leucine zipper transcription factor 2 (BACH2) has been associated with genetic risk to develop type 1 diabetes, in an effect ascribed to the immune system. We evaluated whether BACH2 may also play a role in immune-mediated pancreatic β-cell apoptosis. BACH2 inhibition exacerbated cytokine-induced β-cell apoptosis in human and rodent β-cells by the mitochondrial pathway of cell death, whereas BACH2 overexpression had protective effects. BACH2 silencing and exposure to proinflammatory cytokines increased phosphorylation of the proapoptotic protein JNK1 by upregulation of mitogen-activated protein kinase kinase 7 (MKK7) and downregulation of PTPN2. JNK1 increased phosphorylation of the proapoptotic protein BIM, and both JNK1 and BIM knockdown protected β-cells against cytokine-induced apoptosis in BACH2-silenced cells. The present findings suggest that the type 1 diabetes candidate gene BACH2 regulates proinflammatory cytokine-induced apoptotic pathways in pancreatic β-cells by crosstalk with another candidate gene, PTPN2, and activation of JNK1 and BIM. This clarifies an unexpected and relevant mechanism by which BACH2 may contribute to diabetes.