Golgi stress response reprograms cysteine metabolism to confer cytoprotection in Huntington’s disease

Significance Golgi stress response is emerging as a major stress response pathway although molecular players in the process have not been identified. We show that Golgi stress response induced by the ionophore monensin is mediated by the PERK-ATF4 pathway. We further show that subtoxic levels of monensin precondition cells to respond to future damaging insults. Monensin stimulates the reverse transsulfuration pathway via cystathionine γ-lyase, the biosynthetic enzyme for cysteine, important for redox homeostasis. We have harnessed this pathway to mitigate toxicity associated with cysteine deprivation in Huntington’s disease (HD). These findings are relevant to not only HD, but also other diseases involving redox imbalance. Targeting the molecular controls for restoration of cysteine balance may offer more robust therapeutic avenues for disease management.