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Non-enzymatic cleavage of Hsp90 by oxidative stress leads to actin aggregate formation
- Aging is accompanied by the accumulation of oxidized proteins. To remove them, cells employ the proteasomal and autophagy-lysosomal systems; however, if the clearance rate is inferior to its formation, protein aggregates form as a hallmark of proteostasis loss. In cells, during stress conditions, actin aggregates accumulate leading to impaired proliferation and reduced proteasomal activity, as observed in cellular senescence. The heat shock protein 90 (Hsp90) is a molecular chaperone that binds and protects the proteasome from oxidative inactivation. We hypothesized that in oxidative stress conditions a malfunction of Hsp90 occurs resulting in the aforementioned protein aggregates. Here, we demonstrate that upon oxidative stress Hsp90 loses its function in a highly specific non-enzymatic iron-catalyzed oxidation event and its breakdown product, a cleaved form of Hsp90 (Hsp90cl), acquires a new function in mediating the accumulation of actin aggregates. Moreover, the prevention of Hsp90 cleavage reduces oxidized actin accumulation,Aging is accompanied by the accumulation of oxidized proteins. To remove them, cells employ the proteasomal and autophagy-lysosomal systems; however, if the clearance rate is inferior to its formation, protein aggregates form as a hallmark of proteostasis loss. In cells, during stress conditions, actin aggregates accumulate leading to impaired proliferation and reduced proteasomal activity, as observed in cellular senescence. The heat shock protein 90 (Hsp90) is a molecular chaperone that binds and protects the proteasome from oxidative inactivation. We hypothesized that in oxidative stress conditions a malfunction of Hsp90 occurs resulting in the aforementioned protein aggregates. Here, we demonstrate that upon oxidative stress Hsp90 loses its function in a highly specific non-enzymatic iron-catalyzed oxidation event and its breakdown product, a cleaved form of Hsp90 (Hsp90cl), acquires a new function in mediating the accumulation of actin aggregates. Moreover, the prevention of Hsp90 cleavage reduces oxidized actin accumulation, whereas transfection of the cleaved form of Hsp90 leads to an enhanced accumulation of oxidized actin. This indicates a clear role of the Hsp90cl in the aggregation of oxidized proteins.…
Verfasserangaben: | Jose Pedro CastroORCiD, Raquel Fernando, Sandra ReegGND, Walter MeinlGND, Henrique AlmeidaORCiDGND, Tilman GruneORCiDGND |
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DOI: | https://doi.org/10.1016/j.redox.2019.101108 |
ISSN: | 2213-2317 |
Pubmed ID: | https://pubmed.ncbi.nlm.nih.gov/30660959 |
Titel des übergeordneten Werks (Englisch): | Redox Biology |
Untertitel (Englisch): | A novel gain-of-function mechanism |
Verlag: | Elsevier |
Verlagsort: | Amsterdam |
Publikationstyp: | Wissenschaftlicher Artikel |
Sprache: | Englisch |
Datum der Erstveröffentlichung: | 11.01.2019 |
Erscheinungsjahr: | 2019 |
Datum der Freischaltung: | 12.04.2021 |
Freies Schlagwort / Tag: | Heat shock protein 90; Oxidative stress; Proteasome; Protein aggregates; Protein oxidation |
Band: | 21 |
Seitenanzahl: | 10 |
Fördernde Institution: | German Research Foundation (DFG)German Research Foundation (DFG) |
Organisationseinheiten: | Mathematisch-Naturwissenschaftliche Fakultät / Institut für Ernährungswissenschaft |
DDC-Klassifikation: | 5 Naturwissenschaften und Mathematik / 57 Biowissenschaften; Biologie / 570 Biowissenschaften; Biologie |
Peer Review: | Referiert |
Publikationsweg: | Open Access / Gold Open-Access |
DOAJ gelistet | |
Lizenz (Deutsch): | CC-BY-NC-ND - Namensnennung, nicht kommerziell, keine Bearbeitungen 4.0 International |