Stress-induced protein disaggregation in the endoplasmic reticulum catalysed by BiP
Authors
Farace, Ilaria
Skov, Lise R
Sancho, Teresa P
Paton, Adrienne W
Paton, James C
Fares, Matthew
Paulo, Pedro MR
Publication Date
2022-05-06Journal Title
Nature Communications
Publisher
Nature Publishing Group UK
Volume
13
Issue
1
Language
en
Type
Article
This Version
VoR
Metadata
Show full item recordCitation
Melo, E. P., Konno, T., Farace, I., Awadelkareem, M. A., Skov, L. R., Teodoro, F., Sancho, T. P., et al. (2022). Stress-induced protein disaggregation in the endoplasmic reticulum catalysed by BiP. Nature Communications, 13 (1) https://doi.org/10.1038/s41467-022-30238-2
Description
Funder: This study received Portuguese national funds from FCT - Foundation for Science and Technology through project UIDB/04326/2020, UIDP/04326/2020 and LA/P70101/2020, and from the operational programmes CRESC Algarve 2020 and COMPETE 2020 through project EMBRC.PT ALG-01-0145-FEDER-022121
Funder: UK Medical Research Council
Abstract
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.
Keywords
Article, /631/80/304, /631/80/470/1981, /631/80/470/1463, /631/80/470/2284, /9, /13, /13/31, /13/100, /13/106, /13/109, /14, /14/19, /14/34, /14/63, /38/88, /82/16, article
Sponsorship
Alzheimer's Society (AS-595)
Identifiers
s41467-022-30238-2, 30238
External DOI: https://doi.org/10.1038/s41467-022-30238-2
This record's URL: https://www.repository.cam.ac.uk/handle/1810/336894
Rights
Licence:
http://creativecommons.org/licenses/by/4.0/
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