TY - JOUR
T1 - Golgi stress response reprograms cysteine metabolism to confer cytoprotection in Huntington’s disease
AU - Sbodio, Juan I.
AU - Snyder, Solomon H.
AU - Paul, Bindu D.
N1 - Funding Information:
This work was supported by grants from the US Public Health Service (MH18501) (to S.H.S.) and the CHDI Foundation (to S.H.S. and B.D.P.).
Funding Information:
ACKNOWLEDGMENTS. This work was supported by grants from the US Public Health Service (MH18501) (to S.H.S.) and the CHDI Foundation (to S.H.S. and B.D.P.).
PY - 2018/1/23
Y1 - 2018/1/23
N2 - 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.
AB - 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.
KW - ATF4
KW - CSE
KW - Golgi stress response
KW - Huntington’s disease
KW - Monensin
UR - http://www.scopus.com/inward/record.url?scp=85040867526&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85040867526&partnerID=8YFLogxK
U2 - 10.1073/pnas.1717877115
DO - 10.1073/pnas.1717877115
M3 - Article
C2 - 29317536
AN - SCOPUS:85040867526
VL - 115
SP - 780
EP - 785
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
SN - 0027-8424
IS - 4
ER -