Down-regulation of the islet-specific zinc transporter-8 (ZnT8) protects human insulinoma cells against inflammatory stress

J Biol Chem. 2019 Nov 8;294(45):16992-17006. doi: 10.1074/jbc.RA119.010937. Epub 2019 Oct 7.


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.

Keywords: SLC30A8; Type 1 diabetes; Type 2 diabetes; ZnT8; cytokine; endoplasmic reticulum stress (ER stress); inflammation; insulin; pancreatic beta-cells; solute carrier family 30 member 8; transport; transport metal; transporter; unfolded protein response (UPR); zinc.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Cell Line, Tumor
  • Cytokines / metabolism
  • Down-Regulation*
  • Endoplasmic Reticulum / metabolism
  • Endoplasmic Reticulum Stress / genetics*
  • Gene Knockdown Techniques
  • Humans
  • Inflammation / genetics
  • Inflammation / pathology
  • Insulin / metabolism
  • Insulinoma / pathology*
  • Islets of Langerhans / metabolism*
  • Pancreatic Neoplasms / pathology*
  • Proteasome Endopeptidase Complex / metabolism
  • Protein Transport
  • Zinc Transporter 8 / deficiency
  • Zinc Transporter 8 / genetics*


  • Cytokines
  • Insulin
  • SLC30A8 protein, human
  • Zinc Transporter 8
  • Proteasome Endopeptidase Complex