Grp78 destabilization of infectious prions is strain-specific and modified by multiple factors including accessory chaperones and pH.
| Autor: | Shoup D; Rocky Mountain Laboratories, Laboratory of Neurological Infections and Immunity, National Institute of Allergy & Infectious Diseases, National Institutes of Health, Hamilton, Montana, USA. Electronic address: daniel.shoup@nih.gov., Priola SA; Rocky Mountain Laboratories, Laboratory of Neurological Infections and Immunity, National Institute of Allergy & Infectious Diseases, National Institutes of Health, Hamilton, Montana, USA. |
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| Jazyk: | angličtina |
| Zdroj: | The Journal of biological chemistry [J Biol Chem] 2024 Jun; Vol. 300 (6), pp. 107346. Date of Electronic Publication: 2024 May 06. |
| DOI: | 10.1016/j.jbc.2024.107346 |
| Abstrakt: | Lethal neurodegenerative prion diseases result from the continuous accumulation of infectious and variably protease-resistant prion protein aggregates (PrP D ) which are misfolded forms of the normally detergent soluble and protease-sensitive cellular prion protein. Molecular chaperones like Grp78 have been found to reduce the accumulation of PrP D , but how different cellular environments and other chaperones influence the ability of Grp78 to modify PrP D is poorly understood. In this work, we investigated how pH and protease-mediated structural changes in PrP D from two mouse-adapted scrapie prion strains, 22L and 87V, influenced processing by Grp78 in the presence or absence of chaperones Hsp90, DnaJC1, and Stip1. We developed a cell-free in vitro system to monitor chaperone-mediated structural changes to, and disaggregation of, PrP D . For both strains, Grp78 was most effective at structurally altering PrP D at low pH, especially when additional chaperones were present. While Grp78, DnaJC1, Stip1, and Hsp90 were unable to disaggregate the majority of PrP D from either strain, pretreatment of PrP D with proteases increased disaggregation of 22L PrP D compared to 87V, indicating strain-specific differences in aggregate structure were impacting chaperone activity. Hsp90 also induced structural changes in 87V PrP D as indicated by an increase in the susceptibility of its n-terminus to proteases. Our data suggest that, while chaperones like Grp78, DnaJC1, Stip1, and Hsp90 disaggregate only a small fraction of PrP D , they may still facilitate its clearance by altering aggregate structure and sensitizing PrP D to proteases in a strain and pH-dependent manner. Competing Interests: Conflict of interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.) |
| Databáze: | MEDLINE |
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