Abstract
Protein aggregation is associated with neurodegeneration and various other pathologies. How specific cellular environments modulate the aggregation of disease proteins is not well understood. Here, we investigated how the endoplasmic reticulum (ER) quality control system handles β‐sheet proteins that were designed de novo to form amyloid‐like fibrils. While these proteins undergo toxic aggregation in the cytosol, we find that targeting them to the ER (ER‐β) strongly reduces their toxicity. ER‐β is retained within the ER in a soluble, polymeric state, despite reaching very high concentrations exceeding those of ER‐resident molecular chaperones. ER‐β is not removed by ER‐associated degradation (ERAD) but interferes with ERAD of other proteins. These findings demonstrate a remarkable capacity of the ER to prevent the formation of insoluble β‐aggregates and the secretion of potentially toxic protein species. Our results also suggest a generic mechanism by which proteins with exposed β‐sheet structure in the ER interfere with proteostasis.
Synopsis

The quality control machinery of the ER has a remarkable capacity to maintain otherwise toxic aggregation‐prone proteins in a non‐toxic liquid‐like state, which prevents them from being secreted or retranslocated to the cytoplasm.
Targeting aggregation‐prone proteins to the ER strongly reduces their aggregation and toxicity.
The ER quality control machinery maintains aggregation‐prone proteins in a liquid‐like state.
Aggregation‐prone proteins are prevented from leaving the ER for secretion and are not retranslocated to the cytoplasm for degradation.
Aggregation‐prone proteins in the ER may interfere with the degradation of other misfolded proteins by ERAD.
- Received October 6, 2016.
- Revision received October 19, 2017.
- Accepted October 25, 2017.
- © 2017 The Authors
Subscribers, please sign in with your username and password.
Log in using your username and password
Log in through your institution
Pay Per Article - You may access this article (from the computer you are currently using) for 1 day for US$35.00
Regain Access - You can regain access to a recent Pay per Article purchase if your access period has not yet expired.
EMBO Members please login here to access the journals
Subscribe to the Journal
Recommend to your Librarian