Translocon Declogger Ste24 Protects against IAPP Oligomer-Induced Proteotoxicity.

Cell
Authors
Keywords
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.

Year of Publication
2018
Journal
Cell
Volume
173
Issue
1
Pages
62-73.e9
Date Published
2018 03 22
ISSN
1097-4172
DOI
10.1016/j.cell.2018.02.026
PubMed ID
29526462
PubMed Central ID
PMC5945206
Links
Grant list
K24 DK110550 / DK / NIDDK NIH HHS / United States
T32 GM007287 / GM / NIGMS NIH HHS / United States
R01 HG005084 / HG / NHGRI NIH HHS / United States
R01 HG005853 / HG / NHGRI NIH HHS / United States
R37 GM025874 / GM / NIGMS NIH HHS / United States
R01 GM025874 / GM / NIGMS NIH HHS / United States
DP5 OD017941 / OD / NIH HHS / United States
R21 NS087557 / NS / NINDS NIH HHS / United States
R01 CA175744 / CA / NCI NIH HHS / United States
FDN-143264 / CIHR / Canada