Molecular functions of human zinc transporter-8 in pancreatic beta cells

The long-term goal of our research is to understand how the molecular and cellular functions of zinc transporter-8 (ZnT8) modulate pathophysiologic responses of human pancreatic beta cells to inflammatory stress and autoimmune attack.

ZnT8 is a tissue-specific zinc transporter with an exceedingly high expression level in the insulin-producing beta cells that dedicate ~50% of biosynthetic capacity to insulin production and secretion upon glucose stimulation.

The primary function of ZnT8 is to maintain a high zinc concentration required for proper insulin folding and crystalline packing in the insulin secretory granules, but growing evidence suggests that ZnT8 is a dynamic protein with additional functional roles on the cell surface and at the endoplasmic reticulum (ER) where ZnT8 is a major client protein of unfolded protein response leading to ZnT8 ubiquitination, immunoproteasome degradation and antigenic presentation.

In addition, ZnT8 is a major cell-surface autoantigen targeted by autoreactive B cell in the earlier phase of islet autoimmunity progression to overt type-1 diabetes.

The pleiotropic roles of ZnT8 shape the unique biology of beta cells and modulate their susceptibility to disease-driving inflammatory stress.

Accordingly, human ZnT8 is a major self-antigen targeted for autoimmune destruction of beta cells during acute islet inflammation, and also a major ER stress burden contributing to functional failure of beta cells under chronic, low-grade inflammation.

At present, it is unclear how pathophysiologic responses of human ZnT8 may increase the cell vulnerability to inflammatory stress and autoimmune attack.

The proposed research will elucidate the molecular details of cytokine-induced ZnT8 ubiquitination and degradation (Aim-1), and elucidate the processing and presentation of ZnT8 autoantigen on human beta cells (Aim-2).

Uncovering the molecular mechanisms driving ZnT8 targeting, degradation, and antigenic presentation will inform how ER stress and ZnT8 immunogenicity may be regulated by inflammatory stress to increase the risk of both type-1 and type-2 diabetes.