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Protein aggregation underlies pathologies including neurodegeneration. Aggregates\u2019 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 \u2013 BiP. This work reveals a hitherto unknow, non-redundant strand of the proteostasis-restorative ER stress response.<\/jats:p>","DOI":"10.1038\/s41467-022-30238-2","type":"journal-article","created":{"date-parts":[[2022,5,6]],"date-time":"2022-05-06T06:19:45Z","timestamp":1651817985000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":40,"title":["Stress-induced protein disaggregation in the endoplasmic reticulum catalysed by BiP"],"prefix":"10.1038","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0974-8977","authenticated-orcid":false,"given":"Eduardo Pinho","family":"Melo","sequence":"first","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4983-5805","authenticated-orcid":false,"given":"Tasuku","family":"Konno","sequence":"additional","affiliation":[]},{"given":"Ilaria","family":"Farace","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6898-6310","authenticated-orcid":false,"given":"Mosab Ali","family":"Awadelkareem","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7142-7728","authenticated-orcid":false,"given":"Lise R.","family":"Skov","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5384-1469","authenticated-orcid":false,"given":"Fernando","family":"Teodoro","sequence":"additional","affiliation":[]},{"given":"Teresa P.","family":"Sancho","sequence":"additional","affiliation":[]},{"given":"Adrienne W.","family":"Paton","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9807-5278","authenticated-orcid":false,"given":"James C.","family":"Paton","sequence":"additional","affiliation":[]},{"given":"Matthew","family":"Fares","sequence":"additional","affiliation":[]},{"given":"Pedro M. 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