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Stress-induced protein disaggregation in the endoplasmic reticulum catalysed by BiP.

Published version
Peer-reviewed

Type

Article

Change log

Authors

Melo, Eduardo Pinho  ORCID logo  https://orcid.org/0000-0002-0974-8977
Farace, Ilaria 
Awadelkareem, Mosab Ali  ORCID logo  https://orcid.org/0000-0001-6898-6310

Abstract

Protein synthesis is supported by cellular machineries that ensure polypeptides fold to their native conformation, whilst eliminating misfolded, aggregation prone species. Protein aggregation underlies pathologies including neurodegeneration. Aggregates' formation is antagonised by molecular chaperones, with cytoplasmic machinery resolving insoluble protein aggregates. However, it is unknown whether an analogous disaggregation system exists in the Endoplasmic Reticulum (ER) where ~30% of the proteome is synthesised. Here we show that the ER of a variety of mammalian cell types, including neurons, is endowed with the capability to resolve protein aggregates under stress. Utilising a purpose-developed protein aggregation probing system with a sub-organellar resolution, we observe steady-state aggregate accumulation in the ER. Pharmacological induction of ER stress does not augment aggregates, but rather stimulate their clearance within hours. We show that this dissagregation activity is catalysed by the stress-responsive ER molecular chaperone - BiP. This work reveals a hitherto unknow, non-redundant strand of the proteostasis-restorative ER stress response.

Description

Keywords

Animals, Endoplasmic Reticulum, Endoplasmic Reticulum Chaperone BiP, Endoplasmic Reticulum Stress, Mammals, Molecular Chaperones, Protein Aggregates

Journal Title

Nat Commun

Conference Name

Journal ISSN

2041-1723
2041-1723

Volume Title

13

Publisher

Springer Science and Business Media LLC
Sponsorship
Alzheimer's Society (595, AS-595)