Figure 4.

The Golgi stress response and its intersection with redox homeostasis in Huntington’s disease (HD). (a) Golgi stress response in normal cells. Golgi stress activates PERK, which phosphorylates eIF2α to inhibit general protein synthesis. Only mRNAs such as ATF4 are translated. ATF4 regulates amino acid homeostasis and one of the genes induced by ATF4 is CTH (which encodes the biosynthetic enzyme for cysteine, also called CSE). CSE utilizes cysteine to produce the gaseous signaling molecule hydrogen sulfide (H₂S). H₂S signals by a post-translational modification termed sulfhydration/persulfidation and modulates the activity of target proteins. H₂S stimulates cystine uptake by the cystine transporter, leading to increased cysteine levels in cells. ATF4 also regulates expression of SLC7A11 (xCT), a subunit of the cystine transporter, by activating its transcription through heterodimerization with Nrf2, a master regulator of redox homeostasis. (b) Harnessing the Golgi stress response to elicit cytoprotection in HD. Normal cells express CSE and ATF4 during basal conditions and during stress to produce cysteine. Cysteine is also imported into cells via the cystine transporter, Xc^-. In HD, both basal expression of CSE (regulated by specificity protein1, SP1) as well as stress-induced expression of CSE and the xCT subunit of the cystine transporter by ATF4 are compromised, causing a cysteine deficit which leads to decreased H₂S levels and sulfhydration. When cells are treated with monensin, a Golgi stressor, CSE is induced via the PERK/ATF4 pathway to increase cysteine and H₂S levels and mediate cytoprotection.