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Phospho-BAD BH3 mimicry protects ? cells and restores functional ? cell mass in diabetes.

ABSTRACT: Strategies that simultaneously enhance the survival and glucose responsiveness of insulin-producing ? cells will greatly augment ? cell replacement therapies in type 1 diabetes (T1D). We show that genetic and pharmacologic mimetics of the phosphorylated BCL-2 homology 3 (BH3) domain of BAD impart ?-cell-autonomous protective effects in the face of stress stimuli relevant to ? cell demise in T1D. Importantly, these benefits translate into improved engraftment of donor islets in transplanted diabetic mice, increased ? cell viability in islet grafts, restoration of insulin release, and diabetes reversal. Survival of ? cells in this setting is not merely due to the inability of phospho-BAD to suppress prosurvival BCL-2 proteins but requires its activation of the glucose-metabolizing enzyme glucokinase. Thus, BAD phospho-BH3 mimetics may prove useful in the restoration of functional ? cell mass in diabetes.

SUBMITTER: Ljubicic S

PROVIDER: S-EPMC4991214 | biostudies-literature | 2015 Feb

REPOSITORIES: biostudies-literature

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Phospho-BAD BH3 mimicry protects β cells and restores functional β cell mass in diabetes.

Ljubicic Sanda S Polak Klaudia K Fu Accalia A Wiwczar Jessica J Szlyk Benjamin B Chang Yigang Y Alvarez-Perez Juan C JC Bird Gregory H GH Walensky Loren D LD Garcia-Ocaña Adolfo A Danial Nika N NN

Cell reports 20150129 4

Strategies that simultaneously enhance the survival and glucose responsiveness of insulin-producing β cells will greatly augment β cell replacement therapies in type 1 diabetes (T1D). We show that genetic and pharmacologic mimetics of the phosphorylated BCL-2 homology 3 (BH3) domain of BAD impart β-cell-autonomous protective effects in the face of stress stimuli relevant to β cell demise in T1D. Importantly, these benefits translate into improved engraftment of donor islets in transplanted diabe ...[more]

PMID: 25640178

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Project description:Pathogenicity often differs dramatically among even closely related arenavirus species. For instance, Junín virus (JUNV), the causative agent of Argentine hemorrhagic fever (AHF), is closely related to Tacaribe virus (TCRV), which is normally avirulent in humans. While little is known about how host cell pathways are regulated in response to arenavirus infection, or how this contributes to virulence, these two viruses have been found to differ markedly in their ability to induce apoptosis. However, details of the mechanism(s) governing the apoptotic response to arenavirus infections are unknown. Here we confirm that TCRV-induced apoptosis is mitochondria-regulated, with associated canonical hallmarks of the intrinsic apoptotic pathway, and go on to identify the pro- and anti-apoptotic Bcl-2 factors responsible for regulating this process. In particular, levels of the pro-apoptotic BH3-only proteins Noxa and Puma, as well as their canonical transcription factor p53, were strongly increased. Interestingly, TCRV infection also led to the accumulation of the inactive phosphorylated form of another pro-apoptotic BH3-only protein, Bad (i.e. as phospho-Bad). Knockout of Noxa or Puma suppressed apoptosis in response to TCRV infection, whereas silencing of Bad increased apoptosis, confirming that these factors are key regulators of apoptosis induction in response to TCRV infection. Further, we found that while the highly pathogenic JUNV does not induce caspase activation, it still activated upstream pro-apoptotic factors, consistent with current models suggesting that JUNV evades apoptosis by interfering with caspase activation through a nucleoprotein-mediated decoy function. This new mechanistic insight into the role that individual BH3-only proteins and their regulation play in controlling apoptotic fate in arenavirus-infected cells provides an important experimental framework for future studies aimed at dissecting differences in the apoptotic responses between arenaviruses, their connection to other cell signaling events and ultimately the relationship of these processes to pathogenesis.

Dataset Information

Phospho-BAD BH3 mimicry protects ? cells and restores functional ? cell mass in diabetes.

Publications

Phospho-BAD BH3 mimicry protects β cells and restores functional β cell mass in diabetes.

Similar Datasets

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