RT Journal Article
T1 Loss of glutathione redox homeostasis impairs proteostasis by inhibiting autophagy-dependent protein degradation.
A1 Guerrero-Gómez, David
A1 Mora-Lorca, José Antonio
A1 Sáenz-Narciso, Beatriz
A1 Naranjo-Galindo, Francisco José
A1 Muñoz-Lobato, Fernando
A1 Parrado-Fernández, Cristina
A1 Goikolea, Julen
A1 Cedazo-Minguez, Ángel
A1 Link, Christopher D
A1 Neri, Christian
A1 Sequedo, María Dolores
A1 Vázquez-Manrique, Rafael P
A1 Fernández-Suárez, Elena
A1 Goder, Veit
A1 Pané, Roser
A1 Cabiscol, Elisa
A1 Askjaer, Peter
A1 Cabello, Juan
A1 Miranda-Vizuete, Antonio
AB In the presence of aggregation-prone proteins, the cytosol and endoplasmic reticulum (ER) undergo a dramatic shift in their respective redox status, with the cytosol becoming more oxidized and the ER more reducing. However, whether and how changes in the cellular redox status may affect protein aggregation is unknown. Here, we show that C. elegans loss-of-function mutants for the glutathione reductase gsr-1 gene enhance the deleterious phenotypes of heterologous human, as well as endogenous worm aggregation-prone proteins. These effects are phenocopied by the GSH-depleting agent diethyl maleate. Additionally, gsr-1 mutants abolish the nuclear translocation of HLH-30/TFEB transcription factor, a key inducer of autophagy, and strongly impair the degradation of the autophagy substrate p62/SQST-1::GFP, revealing glutathione reductase may have a role in the clearance of protein aggregates by autophagy. Blocking autophagy in gsr-1 worms expressing aggregation-prone proteins results in strong synthetic developmental phenotypes and lethality, supporting the physiological importance of glutathione reductase in the regulation of misfolded protein clearance. Furthermore, impairing redox homeostasis in both yeast and mammalian cells induces toxicity phenotypes associated with protein aggregation. Together, our data reveal that glutathione redox homeostasis may be central to proteostasis maintenance through autophagy regulation.
YR 2019
FD 2019-02-15
LK http://hdl.handle.net/10668/13573
UL http://hdl.handle.net/10668/13573
LA en
DS RISalud
RD Apr 6, 2025