Abstract
Type 1 diabetes is an autoimmune disorder characterized by chronic inflammation and pancreatic beta-cell loss. Here, we demonstrate that the proinflammatory cytokine interleukin-1beta, combined with interferon-gamma, induces the expression of the Bcl-2 homology 3 (BH3)-only activator PUMA (p53 up-regulated modulator of apoptosis) in beta-cells. Transcriptional activation of PUMA is regulated by nuclear factor-kappaB and endoplasmic reticulum stress but is independent of p53. PUMA activation leads to mitochondrial Bax translocation, cytochrome c release, and caspase-3 cleavage resulting in beta-cell demise. The antiapoptotic Bcl-XL protein is localized mainly at the mitochondria of the beta-cells and antagonizes PUMA action, but Bcl-XL is inactivated by the BH3-only sensitizer DP5/Hrk in cytokine-exposed beta-cells. Moreover, a pharmacological mimic of the BH3-only sensitizer Bad, which inhibits Bcl-XL and Bcl-2, induces PUMA-dependent beta-cell death and potentiates cytokine-induced apoptosis. Our data support a hierarchical activation of BH3-only proteins controlling the intrinsic pathway of beta-cell apoptosis in the context of inflammation and type 1 diabetes.
Highlights
Diabetes affects the quality of life of millions of individuals worldwide [1]
Bcl-2 homology 3 (BH3)-only Activator Protein p53 up-regulated modulator of apoptosis (PUMA) Is Induced by Cytokines in -Cells—The proinflammatory cytokines IL-1 ϩ IFN-␥ induced mitochondrial Bax translocation, cytochrome c release. and caspase-9, -7, and -3 activation in -cells (Fig. 1A and supplemental Fig. S1, A–C), events that characterize the intrinsic pathway of apoptosis [11]
There was a relative dissociation between cytokine-induced PUMA mRNA (Fig. 1D) and protein expression (Fig. 1E), which may be due to delayed protein translation and/or longer protein half-life
Summary
Diabetes affects the quality of life of millions of individuals worldwide [1]. The two main forms of diabetes, type 1 (T1D)4. We demonstrate that the proinflammatory cytokine interleukin-1, combined with interferon-␥, induces the expression of the Bcl-2 homology 3 (BH3)-only activator PUMA (p53 up-regulated modulator of apoptosis) in -cells. PUMA Induces Apoptosis in Pancreatic -Cells subgroup) is to displace activators from prosurvival proteins, allowing them to bind and activate Bax and Bak. Recent data from our group demonstrated that the sensitizer DP5, known as Hrk, is central for -cell demise after exposure to proinflammatory cytokines or chemical ER stressors [16].
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