Loss of glutathione redox homeostasis impairs proteostasis by inhibiting autophagy-dependent protein degradation

Abstract

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 mutants lacking 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.

Loss of glutathione redox homeostasis impairs proteostasis by inhibiting autophagy-dependent protein degradation

“…In agreement, genetic disruption of autophagy in gsr-1 mutants expressing aggregation prone proteins resulted in strong synthetic developmental phenotypes and in sorne cases lethality. Downregulation of glutathione reductase and GSH levels in both yeast and mammalian cell models also caused phenotypes associated to protein aggregation and impaired TFEB nuclear translocation [3]. Together, this study demonstrates a novel, evolutionarily conserved role of glutathione redox homeostasis in proteostasis maintenance through autophagy regulation .…”

“…lmportantly, gsr-1 dependent proteostatic disruption is also found in C. elegans strains expressing endogenous UNC-52 and LET-60 aggregate-prone metastable proteins. This deleterious effect is largely phenocopied by the GSH depleting agent diethyl ma leate [3].Protein aggregates can be disposed by autophagy and consistent with a role of GSR-1 in this process, gsr-1 mutants abolish nuclear translocation of the TFEB/HLH-30 transcription factor (a key mediator of autophagy induction) and strongly impair the degradation of the autophagy substrate p62/SQST -1 ::GFP. In agreement, genetic disruption of autophagy in gsr-1 mutants expressing aggregation prone proteins resulted in strong synthetic developmental phenotypes and in sorne cases lethality.…”

“…96:446-61 . {3] Guerrero-Gómez O, et al (2019) Loss of qlutathtone redox homeostasis impairs proteostasis bv inhibitinq autophaqy-dependent protein deqradation. Ce// Oeath Oiffer.…”

“…lmportantly, gsr-1 dependent proteostatic disruption is also found in C. elegans strains expressing endogenous UNC-52 and LET-60 aggregate-prone metastable proteins. This deleterious effect is largely phenocopied by the GSH depleting agent diethyl ma leate [3].…”