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Cell. 2018 Mar 22;173(1):62-73.e9. doi: 10.1016/j.cell.2018.02.026. Epub 2018 Mar 8.

Translocon Declogger Ste24 Protects against IAPP Oligomer-Induced Proteotoxicity.

Author information

1
Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA. Electronic address: can.kayatekin@gmail.com.
2
Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
3
Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.
4
Programs in Metabolism and Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Center for Human Genetic Research, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA.
5
Bioinformatics and Computational Biology Graduate Program, University of Minnesota-Twin Cities, Minneapolis, MN 55455, USA.
6
Donnelly Centre, University of Toronto, Toronto, ON M5S 3E1, Canada.
7
Department of Computer Science and Engineering, University of Minnesota-Twin Cities, Minneapolis, MN 55455, USA.
8
Programs in Metabolism and Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Center for Human Genetic Research, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Diabetes Research Center, Diabetes Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Medicine, Harvard Medical School, Boston, MA 02114, USA.
9
Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA; Massachusetts Institute of Technology, Cambridge, MA 02142, USA; Howard Hughes Medical Institute, Cambridge, MA 02139, USA.

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.

KEYWORDS:

IAPP; ZMPSTE24; aggregation; amylin; diabetes; protein folding; proteotoxicity; yeast

PMID:
29526462
PMCID:
PMC5945206
DOI:
10.1016/j.cell.2018.02.026
[Indexed for MEDLINE]
Free PMC Article

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