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- W2979968002 abstract "Zinc transporter-8 (ZnT8) primarily functions as a zinc-sequestrating transporter in the insulin-secretory granules (ISGs) of pancreatic β-cells. Loss-of-function mutations in ZnT8 are associated with protection against type-2 diabetes (T2D), but the protective mechanism is unclear. Here, we developed an in-cell ZnT8 assay to track endogenous ZnT8 responses to metabolic and inflammatory stresses applied to human insulinoma EndoC-βH1 cells. Unexpectedly, high glucose and free fatty acids did not alter cellular ZnT8 levels, but proinflammatory cytokines acutely, reversibly, and gradually down-regulated ZnT8. Approximately 50% of the cellular ZnT8 was localized to the endoplasmic reticulum (ER), which was the primary target of the cytokine-mediated ZnT8 down-regulation. Transcriptome profiling of cytokine-exposed β-cells revealed an adaptive unfolded protein response (UPR) including a marked immunoproteasome activation that coordinately degraded ZnT8 and insulin over a 1,000-fold cytokine concentration range. RNAi-mediated ZnT8 knockdown protected cells against cytokine cytotoxicity, whereas inhibiting immunoproteasomes blocked cytokine-induced ZnT8 degradation and triggered a transition of the adaptive UPR to cell apoptosis. Hence, cytokine-induced down-regulation of the ER ZnT8 level promotes adaptive UPR, acting as a protective mechanism that decongests the ER burden of ZnT8 to protect β-cells from proapoptotic UPR during chronic low-grade inflammation." @default.
- W2979968002 created "2019-10-18" @default.
- W2979968002 creator A5039239098 @default.
- W2979968002 creator A5049014516 @default.
- W2979968002 date "2019-11-01" @default.
- W2979968002 modified "2023-09-29" @default.
- W2979968002 title "Down-regulation of the islet-specific zinc transporter-8 (ZnT8) protects human insulinoma cells against inflammatory stress" @default.
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- W2979968002 doi "https://doi.org/10.1074/jbc.ra119.010937" @default.
- W2979968002 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/6851310" @default.
- W2979968002 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/31591269" @default.
- W2979968002 hasPublicationYear "2019" @default.
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