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Signaling by IL-1β+IFN-γ and ER stress converge on DP5/Hrk activation: a novel mechanism for pancreatic β-cell apoptosis

2009; Springer Nature; Volume: 16; Issue: 11 Linguagem: Inglês

10.1038/cdd.2009.99

1476-5403

Esteban N. Gurzov, Fernanda Ortis, Daniel A. Cunha, Guillermo Gosset, M Li, Alessandra K. Cardozo, Décio L. Eizirik,

Diabetes and associated disorders

Chronic inflammation and pro-inflammatory cytokines are important mediators of pancreatic β-cell destruction in type 1 diabetes (T1D). We presently show that the cytokines IL-1β+IFN-γ and different ER stressors activate the Bcl-2 homology 3 (BH3)-only member death protein 5 (DP5)/harakiri (Hrk) resulting in β-cell apoptosis. Chemical ER stress-induced DP5 upregulation is JNK/c-Jun-dependent. DP5 activation by cytokines also involves JNK/c-Jun phosphorylation and is antagonized by JunB. Interestingly, cytokine-inducted DP5 expression precedes ER stress: mitochondrial release of cytochrome c and ER stress are actually a consequence of enhanced DP5 activation by cytokine-mediated nitric oxide formation. Our findings show that DP5 is central for β-cell apoptosis after different stimuli, and that it can act up- and downstream of ER stress. These observations contribute to solve two important questions, namely the mechanism by which IL-1β+IFN-γ induce β-cell death and the nature of the downstream signals by which ER stress ‘convinces’ β-cells to trigger apoptosis.