ZnT8 is a major autoantigen targeted by the autoimmune system in T1D. ​ ZnT8 loss-of-function mutations in humans offer robust protection against T2D without adverse effects. In our quest to translate "experiments of nature" – naturally occurring mutations that impart disease resistance by modifying a specific protein target – into ZnT8-specific therapeutics, we have advanced ZnT8 research along a continuum of increasing insights, marked by the following milestones:

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1. Elucidating the structural basis and functional regulation of zinc transport at the molecular level (1,2).

2. Discovering the dynamic process of ZnT8 subcellular distribution and regulation by pathophysiologic stimuli (3, 4). 

3. Identifying cell-surface ZnT8 autoantibodies in a subset of patients with T1D (5).

4. Isolating a cell-surface ZnT8 autoantibody (mAb43) with islet homing ability upon systemic administration (6). 

5. Demonstrating safety and sustained mAb43 efficacy in preventing and reversing autoimmune diabetes in mice (7).

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References

1. Lu, M., and Fu, D. (2007) Structure of the zinc transporter YiiP. Science. 317, 1746-1748.

2. Gupta, S., Chai, J., Cheng, J., D'Mello, R., Chance, M. R., and Fu, D. (2014) Visualizing the kinetic power stroke that drives proton-coupled    zinc(II) transport. Nature 512, 101-104

3. Huang, Q., Merriman, C., Zhang, H., and Fu, D. (2017) Coupling of Insulin Secretion and Display of a Granule-resident Zinc Transporter ZnT8 on the Surface of Pancreatic Beta Cells. J Biol Chem 292, 4034-4043

4. Merriman, C., and Fu, D. (2019) Down-regulation of the islet-specific zinc transporter-8 (ZNT8) protects human insulinoma cells against inflammatory stress. J Biol Chem 294(45):16992-17006.

5. Gu, Y., Merriman, C., Guo, Z., Jia, X., Wenzlau, J., Li, H., Li, H., Rewers, M., Yu, L., and Fu, D. (2021) Novel autoantibodies to the beta-cell surface epitopes of ZnT8 in patients progressing to type-1 diabetes. J Autoimmunity 122, 102677

6. Guo, Z., Kasinathan, D., Merriman, C., Nakayama, M., Li, H., Li, H., Xu, C., Wong, G. W., Yu, L., Golson, M. L., and Fu, D. (2023) Cell-Surface Autoantibody Targets Zinc Transporter-8 (ZnT8) for In Vivo beta-Cell Imaging and Islet-Specific Therapies. Diabetes 72, 184-195

7. Kasinathan, D., Guo, Z., Sarver, D. C., Wong, G. W., Yun, S., Michel, A., Yu, L., Golson, M. L., and Fu, D. (2024) Cell-surface ZnT8 antibody prevents and reverses autoimmune diabetes in mice. Diabetes In press

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