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  - 
TY  - JOUR
A1  - Fernando, Raquel
A1  - Drescher, Cathleen
A1  - Nowotny, Kerstin
A1  - Grune, Tilman
A1  - Castro, Jose Pedro
T1  - Impaired proteostasis during skeletal muscle aging
JF  - Free radical biology and medicine : the official journal of the Oxygen Society, a constituent member of the International Society for Free Radical Research
N2  - Aging is a complex phenomenon that has detrimental effects on tissue homeostasis. The skeletal muscle is one of the earliest tissues to be affected and to manifest age-related changes such as functional impairment and the loss of mass. Common to these alterations and to most of tissues during aging is the disruption of the proteostasis network by detrimental changes in the ubiquitin-proteasomal system (UPS) and the autophagy-lysosomal system (ALS). In fact, during aging the accumulation of protein aggregates, a process mainly driven by increased levels of oxidative stress, has been observed, clearly demonstrating UPS and ALS dysregulation. Since the UPS and ALS are the two most important pathways for the removal of misfolded and aggregated proteins and also of damaged organelles, we provide here an overview on the current knowledge regarding the connection between the loss of proteostasis and skeletal muscle functional impairment and also how redox regulation can play a role during aging. Therefore, this review serves for a better understanding of skeletal muscle aging in regard to the loss of proteostasis and how redox regulation can impact its function and maintenance.
KW  - Skeletal muscle
KW  - Proteostasis
KW  - Proteasome and lysosome
KW  - Oxidative stress
KW  - Redox regulation
KW  - Aging
Y1  - 2018
U6  - https://doi.org/10.1016/j.freeradbiomed.2018.08.037
SN  - 0891-5849
SN  - 1873-4596
VL  - 132
SP  - 58
EP  - 66
PB  - Elsevier
CY  - New York
ER  -