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

Eduardo Pinho Melo (), Tasuku Konno, Ilaria Farace, Mosab Ali Awadelkareem, Lise R. Skov, Fernando Teodoro, Teresa P. Sancho, Adrienne W. Paton, James C. Paton, Matthew Fares, Pedro M. R. Paulo, Xin Zhang and Edward Avezov ()
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Eduardo Pinho Melo: University of Cambridge
Tasuku Konno: University of Cambridge
Ilaria Farace: University of Cambridge
Mosab Ali Awadelkareem: University of Cambridge
Lise R. Skov: University of Cambridge
Fernando Teodoro: Universidade do Algarve, Campus de Gambelas
Teresa P. Sancho: Universidade do Algarve, Campus de Gambelas
Adrienne W. Paton: University of Adelaide
James C. Paton: University of Adelaide
Matthew Fares: University Park
Pedro M. R. Paulo: Universidade de Lisboa, Av. Rovisco Pais
Xin Zhang: University Park
Edward Avezov: University of Cambridge

Nature Communications, 2022, vol. 13, issue 1, 1-11

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.

Date: 2022
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DOI: 10.1038/s41467-022-30238-2

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