Journal Article

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

Zhang, Xin, Paulo, Pedro M. R, Paton, James C, Paton, Adrienne W, Fares, Matthew, Farace, Ilaria, Melo, Eduardo, Skov, Lise R, Teodoro, Fernando, Konno, Tasuku, Awadelkareem, Mosab Ali, Sancho, Teresa, Avezov, Edward

2022

Overview

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.

• Publisher: Nature Portfolio,Nature Publishing Group UK,Nature Publishing Group
• Subject: 13 / 13/100 / 13/106 / 13/109 / 13/31 / 14 / 14/19 / 14/34 / 14/63 / 38/88 / 631/80/304 / 631/80/470/1463 / 631/80/470/1981 / 631/80/470/2284 / 82/16 / Agglomeration / Aggregates / Animals / BiP protein / Chemical synthesis / Disaggregation / Endoplasmic reticulum / Endoplasmic Reticulum - metabolism / Endoplasmic Reticulum Chaperone BiP / Endoplasmic Reticulum Stress / Humanities and Social Sciences / Mammals - metabolism / Molecular Chaperones - metabolism / multidisciplinary / Neurodegeneration / Polypeptides / Protein Aggregates / Protein biosynthesis / Protein folding / Protein interaction / Protein synthesis / Proteins / Proteomes / Science / Science (multidisciplinary)