Stress-induced protein disaggregation in the endoplasmic reticulum catalysed by BiP.
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Authors
Farace, Ilaria
Sancho, Teresa P
Paton, Adrienne W
Fares, Matthew
Paulo, Pedro MR
Publication Date
2022-05-06Journal Title
Nat Commun
ISSN
2041-1723
Publisher
Springer Science and Business Media LLC
Type
Article
This Version
VoR
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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.. Nat Commun https://doi.org/10.1038/s41467-022-30238-2
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.
Identifiers
External DOI: https://doi.org/10.1038/s41467-022-30238-2
This record's URL: https://www.repository.cam.ac.uk/handle/1810/337098
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