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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. Aggregation of misfolded proteins underlie dementias. Here, the authors show that stressed cells activate an innate mechanism to resolve aggregates of defective proteins in the endoplasmic reticulum, where a third of cellular proteins are produced.

Protein synthesis is supported by cellular machineries that ensure polypeptides fold to their native three-dimensional conformation with high fidelity whilst eliminating misfolded, aggregation-prone species. While protein aggregates can contribute to pathologies exemplified by Alzheimer’s and Parkinson’s diseases, their abundance is normally minimised by molecular chaperones such as HSP70/90, which promote native folding and drive the recycling of aberrantly folded species. Cytoplasmic chaperones (e.g. HSP70/40) can resolve insoluble protein aggregates should the preventive mechanisms falter. However, it is unknown whether an analogous disaggregation system is needed and 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 that accumulate upon expression of metastable proteins. Utilising a purpose-developed protein aggregation probing system with a sub-organellar resolution, we observed steady-state aggregate accumulation in the ER. Strikingly, pharmacological induction of ER stress did not augment aggregates but rather stimulated their clearance within hours. We found that this disaggregation activity was catalysed by the stress-responsive ER molecular chaperone – BiP. Its elimination abolished the disaggregation activity in cells. Further, we reconstructed the disaggregation-reaction in-vitro by a minimal system of ATP-fuelled BiP and its J-protein cofactor. These data reveal a hitherto unknown, non-redundant function of the ER stress response. Thus, our findings may facilitate the identification of aggregation-antagonising strategies and rationalising the age-dependent protein misfolding pathology. ER stress induction activates a protein disaggregation machinery, powered by BiP – an abundant ER chaperone, revealed by a FLIM-based protein aggregation monitoring in live cells.