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Non-enzymatic cleavage of Hsp90 by oxidative stress leads to actin aggregate formation: A novel gain-of-function mechanism.

ABSTRACT: 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.

SUBMITTER: Castro JP

PROVIDER: S-EPMC6348241 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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Non-enzymatic cleavage of Hsp90 by oxidative stress leads to actin aggregate formation: A novel gain-of-function mechanism.

Castro José Pedro JP Fernando Raquel R Reeg Sandra S Meinl Walter W Almeida Henrique H Grune Tilman T

Redox biology 20190111

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 ...[more]

PMID: 30660959

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Dataset Information

Non-enzymatic cleavage of Hsp90 by oxidative stress leads to actin aggregate formation: A novel gain-of-function mechanism.

Publications

Non-enzymatic cleavage of Hsp90 by oxidative stress leads to actin aggregate formation: A novel gain-of-function mechanism.

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