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

Golgi stress response is emerging as a physiologic process of comparable importance to endoplasmic reticulum (ER) and mitochondrial stress responses. However, unlike ER stress, the identity of the signal transduction pathway involved in the Golgi stress response has been elusive. We show that the Go...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2018-01, Vol.115 (4), p.780-785
Main Authors: Sbodio, Juan I., Snyder, Solomon H., Paul, Bindu D.
Format: Article
Language:English
Subjects:
Acids
Activating transcription factor 4
Amino acids
Biological Sciences
Cells
Cysteine
Depletion
Endoplasmic reticulum
Golgi apparatus
Homeostasis
Huntington's disease
Huntingtons disease
Medical treatment
Metabolism
Mitochondria
Monensin
Neurodegenerative diseases
Preconditioning
Signal transduction
Signaling
Stress
Stresses
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Summary:Golgi stress response is emerging as a physiologic process of comparable importance to endoplasmic reticulum (ER) and mitochondrial stress responses. However, unlike ER stress, the identity of the signal transduction pathway involved in the Golgi stress response has been elusive. We show that the Golgi stressor monensin acts via the PKR-like ER kinase/Activating Transcription Factor 4 pathway. ATF4 is the master regulator of amino acid metabolism, which is induced during amino acid depletion and other forms of stress. One of the genes regulated by ATF4 is the biosynthetic enzyme for cysteine, cystathionine γ-lyase (CSE), which also plays central roles in maintenance of redox homeostasis. Huntington’s disease (HD), a neurodegenerative disorder, is associated with disrupted cysteine metabolism caused by depletion of CSE leading to abnormal redox balance and stress response. Thus, restoring CSE function and cysteine disposition may be beneficial in HD. Accordingly, we harnessed the monensin-ATF4–signaling cascade to stimulate CSE expression by preconditioning cells with monensin, which restores cysteine metabolism and an optimal stress response in HD. These findings have implications for treatment of HD and other diseases associated with redox imbalance and dysregulated ATF4 signaling.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.1717877115