Limited detoxification capacity often directs aggregation-prone, potentially hazardous, misfolded proteins to be deposited in designated cytosolic compartments known as ‘aggresomes’. The roles of aggresomes as cellular quality control centers, and the cellular origin of the deposits contained within these structures, remain to be characterized. Here, we utilized the observation that the prion protein (PrP, also known as PRNP) accumulates in aggresomes following the inhibition of folding chaperones, members of the cyclophilin family, to address these questions. We found that misfolded PrP molecules must pass through the endoplasmic reticulum (ER) in order to be deposited in aggresomes, that the Golgi plays no role in this process and that cytosolic PrP species are not deposited in pre-existing aggresomes. Prior to their deposition in the aggresome, PrP molecules lose the ER localization signal and have to acquire a GPI anchor. Our discoveries indicate that PrP aggresomes are cytosolic overflow deposition centers for the ER quality control mechanisms and highlight the importance of these structures for the maintenance of protein homeostasis within the ER.
The authors declare no competing or financial interests.
E.C. and T.D. initiated this study and performed the experimental work. R.R. assisted with plasmid construction and T.B.-G. helped with processing mouse brains. D.H. developed and provided Decatransin. J.C.M. and W.A.C. created cyclophilin-B-knockout mice. E.C. and T.D. wrote the manuscript, which was reviewed and approved by all authors.
This study was generously supported by the European Research Council (ERC) [grant number E.C. 281010].
Supplementary information available online at http://jcs.biologists.org/lookup/doi/10.1242/jcs.186981.supplemental
- Received January 27, 2016.
- Accepted August 13, 2016.
- © 2016. Published by The Company of Biologists Ltd