title: Mammalian target of rapamycin complex 1 (mTORC1)-mediated phosphorylation stabilizes ISCU protein: implications for iron metabolism.
abstract: 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.
authors.affiliation: Division of Neonatology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA. lap@email.chop.edu
authors.forename: Ping
authors.initials: P
authors.lastname: La
authors.forename: Guang
authors.initials: G
authors.lastname: Yang
authors.forename: Phyllis A
authors.initials: PA
authors.lastname: Dennery
mesh_terms: D041721:3T3-L1 Cells; D000818:Animals; D006367:HeLa Cells; D006706:Homeostasis / Q000502:physiology; D006801:Humans; D007501:Iron / Q000378:metabolism*; D007506:Iron-Sulfur Proteins / Q000235:genetics / Q000378:metabolism*; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D046912:Multiprotein Complexes; D010766:Phosphorylation / Q000502:physiology; D055550:Protein Stability; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: C506160:ISCU protein, human; D007506:Iron-Sulfur Proteins; C523690:IscU protein, mouse; D046912:Multiprotein Complexes; D011506:Proteins; D007501:Iron; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases
keywords: ISCU; Iron-sulfur Clusters; Iron-sulfur Protein; Metabolism; Phosphorylation; Tuberous Sclerosis (Tsc); mTOR