Mammalian Target of Rapamycin Complex 1 (mTORC1)-mediated Phosphorylation Stabilizes ISCU Protein

The scaffold protein ISCU facilitates the assembly of iron-sulfur clusters (ISCs), which are essential cofactors for many vital metabolic processes. The mTOR pathways are central to nutrient and energy-sensing networks. Here, we demonstrate that mTORC1 associates with ISCU and phosphorylates ISCU at...

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Bibliographic Details
Published in:The Journal of biological chemistry 2013-05, Vol.288 (18), p.12901-12909
Main Authors: La, Ping, Yang, Guang, Dennery, Phyllis A.
Format: Article
Language:English
Subjects:
Iron-sulfur Clusters
Iron-sulfur Protein
ISCU
Metabolism
mTOR
Phosphorylation
Tuberous Sclerosis (Tsc)
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Summary:The scaffold protein ISCU facilitates the assembly of iron-sulfur clusters (ISCs), which are essential cofactors for many vital metabolic processes. The mTOR pathways are central to nutrient and energy-sensing networks. Here, we demonstrate that mTORC1 associates with ISCU and phosphorylates ISCU at serine 14. This phosphorylation stabilized ISCU protein. Insufficiency of ISCU triggered by mTORC1 inhibition prevented ISC assembly. Sustained ISCU protein levels enhanced by mTORC1 sensitized TSC2-null cells to iron deprivation due to constitutive ISC biogenesis-triggered iron demand, which outstrips supply. We conclude that the mTORC1 pathway serves to modulate iron metabolism and homeostasis, and we speculate that iron deprivation may be an adjunct in the treatment of cancers characterized by constitutive mTORC1 activation. Background: ISCU facilitates assembly of iron-sulfur clusters (ISCs), the essential metabolic cofactors. Results: mTORC1, a nutrient-sensing kinase, phosphorylates and stabilizes ISCU protein. Conclusion: Through mTORC1, metabolic status affects ISC biogenesis. Significance: This report is the first to show that ISC assembly is a part of mTORC1-modulated anabolism, and via mTORC1, coordinates with other biosynthetic processes to ensure cell growth and survival.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M112.424499