TY  - JOUR
A1  - Castro, Jose Pedro
A1  - Fernando, Raquel
A1  - Reeg, Sandra
A1  - Meinl, Walter
A1  - Almeida, Henrique
A1  - Grune, Tilman
T1  - Non-enzymatic cleavage of Hsp90 by oxidative stress leads to actin aggregate formation
BT  - A novel gain-of-function mechanism
JF  - Redox Biology
N2  - 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.
KW  - Oxidative stress
KW  - Protein oxidation
KW  - Heat shock protein 90
KW  - Proteasome
KW  - Protein aggregates
Y1  - 2019
U6  - https://doi.org/10.1016/j.redox.2019.101108
SN  - 2213-2317
VL  - 21
PB  - Elsevier
CY  - Amsterdam
ER  -