Abstract
Aggregates of human islet amyloid polypeptide (IAPP) in the pancreas of patients with type 2 diabetes (T2D) are thought to contribute to β cell dysfunction and death. To understand how IAPP harms cells and how this might be overcome, we created a yeast model of IAPP toxicity. Ste24, an evolutionarily conserved protease that was recently reported to degrade peptides stuck within the translocon between the cytoplasm and the endoplasmic reticulum, was the strongest suppressor of IAPP toxicity. By testing variants of the human homolog, ZMPSTE24, with varying activity levels, the rescue of IAPP toxicity proved to be directly proportional to the declogging efficiency. Clinically relevant ZMPSTE24 variants identified in the largest database of exomes sequences derived from T2D patients were characterized using the yeast model, revealing 14 partial loss-of-function variants, which were enriched among diabetes patients over 2-fold. Thus, clogging of the translocon by IAPP oligomers may contribute to β cell failure. A combination of yeast- and human-genetics studies explains how aggregates of human islet amyloid polypeptide interfere with protein translocon function to drive β cell dysfunction in type 2 diabetes.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 62-73.e9 |
| Journal | Cell |
| Volume | 173 |
| Issue number | 1 |
| DOIs | |
| State | Published - Mar 22 2018 |
Bibliographical note
Funding Information:This work is dedicated to the memory of our dear friend and mentor, Susan Lindquist, from whom we have learned so much and without whom this work would not have been possible. We thank A. Muthukumar, D. Melton, Y. Freyzon, L. Bayru, L. Clayton, B. Bevis, B.K. Wagner, A. Vetere, A. Haque, E. Hallaçlı, G. Newby, I. Oderberg, and G. Bell, along with members of the Lindquist, Florez, and Melton laboratories for materials, insightful discussions, and comments. We thank the Schuldiner lab for generously providing ZMPSTE24 plasmids and the El-Samad lab for generously providing plasmids for the estradiol-inducible expression system. This work was supported by grants from the Whitehead Institute for Biomedical Research , the Picower Institute at MIT, the University of Texas, M.D. Anderson Center , the Howard Hughes Medical Institute , the Glenn Foundation for Medical Research , the Eleanor Schwartz Charitable Foundation , the Edward N. and Della L. Thome Foundation , the JPB Foundation , the Robert A. and Renee E. Belfer Foundation , the NIH ( GM025874 , R01HG005084 , R01HG005853 ), Canadian Institute of Health Research ( FDN-143264 ), and the Department of Defense ( W81XWH14-1-0157 ). G.G. was supported by a fellowship from the American Italian Cancer Foundation and the NIH ( R0 CA175744 ). D.L. was supported by a Fellowship from the American Parkinson's Disease Foundation and the NIH ( R21 NS087557 ). P.N. was supported by a Fellowship from the Helen Hay Whitney Foundation .
Publisher Copyright:
© 2018 Elsevier Inc.
Keywords
- IAPP
- ZMPSTE24
- aggregation
- amylin
- diabetes
- protein folding
- proteotoxicity
- yeast
