Non-enzymatic cleavage of Hsp90 by oxidative stress leads to actin aggregate formation: A novel gain-of-function mechanism
| Autor: | Tilman Grune, Henrique Almeida, Raquel Fernando, José Pedro Castro, Sandra Reeg, Walter Meinl |
|---|---|
| Přispěvatelé: | Instituto de Investigação e Inovação em Saúde |
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Protein aggregates Proteasome Endopeptidase Complex Iron Clinical Biochemistry Actins / genetics Protein aggregation Protein oxidation Cleavage (embryo) Biochemistry Models Biological Protein Aggregation Pathological Cell Line 03 medical and health sciences 0302 clinical medicine Heat shock protein HSP90 Heat-Shock Proteins / metabolism Humans HSP90 Heat-Shock Proteins Heat shock protein 90 lcsh:QH301-705.5 Actin Actins / metabolism Oxidative Stress / genetics lcsh:R5-920 biology Proteasome Chemistry Proteasome Endopeptidase Complex / metabolism Iron / metabolism Organic Chemistry Hsp90 Actins Oxidative Stress 030104 developmental biology Proteostasis lcsh:Biology (General) Oxidative stress HSP90 Heat-Shock Proteins / genetics Gain of Function Mutation Proteolysis biology.protein Biophysics lcsh:Medicine (General) 030217 neurology & neurosurgery Research Paper |
| Zdroj: | Redox Biology, Vol 21, Iss, Pp-(2019) Redox Biology |
| ISSN: | 2213-2317 |
| Popis: | 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. Graphical abstract fx1 |
| Databáze: | OpenAIRE |
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