title: BACH2, a candidate risk gene for type 1 diabetes, regulates apoptosis in pancreatic β-cells via JNK1 modulation and crosstalk with the candidate gene PTPN2.
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.
authors.affiliation: Laboratory of Experimental Medicine, Université Libre de Bruxelles Center for Diabetes Research, Medical Faculty, Université Libre de Bruxelles, Brussels, Belgium.
authors.forename: Laura
authors.initials: L
authors.lastname: Marroquí
authors.affiliation: Laboratory of Experimental Medicine, Université Libre de Bruxelles Center for Diabetes Research, Medical Faculty, Université Libre de Bruxelles, Brussels, BelgiumEndocrinology and Diabetes Research Group, BioCruces Health Research Institute and Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders, Barakaldo, Spain.
authors.forename: Izortze
authors.initials: I
authors.lastname: Santin
authors.affiliation: Laboratory of Experimental Medicine, Université Libre de Bruxelles Center for Diabetes Research, Medical Faculty, Université Libre de Bruxelles, Brussels, Belgium.
authors.forename: Reinaldo Sousa
authors.initials: RS
authors.lastname: Dos Santos
authors.affiliation: Department of Endocrinology and Metabolism, Metabolic Unit, University of Pisa, Pisa, Italy.
authors.forename: Lorella
authors.initials: L
authors.lastname: Marselli
authors.affiliation: Department of Endocrinology and Metabolism, Metabolic Unit, University of Pisa, Pisa, Italy.
authors.forename: Piero
authors.initials: P
authors.lastname: Marchetti
authors.affiliation: Laboratory of Experimental Medicine, Université Libre de Bruxelles Center for Diabetes Research, Medical Faculty, Université Libre de Bruxelles, Brussels, Belgium deizirik@ulb.ac.be.
authors.forename: Decio L
authors.initials: DL
authors.lastname: Eizirik
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics*; D050976:Basic-Leucine Zipper Transcription Factors / Q000235:genetics / Q000502:physiology*; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism / Q000494:pharmacology; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics*; D004843:Epistasis, Genetic; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism / Q000494:pharmacology; D050417:Insulin-Secreting Cells / Q000502:physiology*; D008297:Male; D008875:Middle Aged; D048055:Mitogen-Activated Protein Kinase 8 / Q000378:metabolism*; D054578:Protein Tyrosine Phosphatase, Non-Receptor Type 2 / Q000235:genetics*; D051381:Rats; D017208:Rats, Wistar; D012306:Risk
chemical_list: C491123:BACH2 protein, human; D050976:Basic-Leucine Zipper Transcription Factors; D016207:Cytokines; D018836:Inflammation Mediators; D048055:Mitogen-Activated Protein Kinase 8; C516649:PTPN2 protein, human; D054578:Protein Tyrosine Phosphatase, Non-Receptor Type 2