High Capacity of the Endoplasmic Reticulum to Prevent Secretion and Aggregation of Amyloidogenic Proteins

Overview

Journal EMBO J

Specialties Biotechnology
Molecular Biology

Date 2017 Dec 17

PMID 29247078

Citations 19

Authors

Lisa Vincenz-Donnelly

Hauke Holthusen

Roman Korner

Erik C Hansen

Jenny Presto

Jan Johansson

Ritwick Sawarkar

F Ulrich Hartl

Mark S Hipp

Affiliations

Soon will be listed here.

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 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.

Citing Articles

APP-C31: An Intracellular Promoter of Both Metal-Free and Metal-Bound Amyloid-β Aggregation and Toxicity in Alzheimer's Disease.

Nam E, Lin Y, Park J, Do H, Han J, Jeong B Adv Sci (Weinh). 2023; 11(4):e2307182.

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Genetic inactivation of essential reveals an isolated transcriptional stress response selectively induced by protein misfolding.

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The unfolded protein response of the endoplasmic reticulum supports mitochondrial biogenesis by buffering nonimported proteins.

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Metal-Binding Proteins Cross-Linking with Endoplasmic Reticulum Stress in Cardiovascular Diseases.

Li K, Li Y, Ding H, Chen J, Zhang X J Cardiovasc Dev Dis. 2023; 10(4).

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Rhomboid protease RHBDL4 promotes retrotranslocation of aggregation-prone proteins for degradation.

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