High capacity of the endoplasmic reticulum to prevent secretion and aggregation of amyloidogenic proteins

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. Graphical Abstract While amyloidogenic proteins drive formation of toxic aggregates in the cytoplasm, they are tolerated in the ER by being kept in a liquid‐like state, illustrating compartment‐specific responses to protein misfolding.