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

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Melo, Eduardo Pinho  ORCID logo
Farace, Ilaria 
Awadelkareem, Mosab Ali  ORCID logo

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.


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

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
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Nature Communications
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Nature Publishing Group UK
Alzheimer's Society (AS-595)