Mammalian target of rapamycin complex 1 (mTORC1)-mediated phosphorylation stabilizes ISCU protein: implications for iron metabolism

J Biol Chem. 2013 May 3;288(18):12901-9. doi: 10.1074/jbc.M112.424499. Epub 2013 Mar 18.

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.

Keywords: ISCU; Iron-sulfur Clusters; Iron-sulfur Protein; Metabolism; Phosphorylation; Tuberous Sclerosis (Tsc); mTOR.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • 3T3-L1 Cells
  • Animals
  • HeLa Cells
  • Homeostasis / physiology
  • Humans
  • Iron / metabolism*
  • Iron-Sulfur Proteins / genetics
  • Iron-Sulfur Proteins / metabolism*
  • Mechanistic Target of Rapamycin Complex 1
  • Mice
  • Multiprotein Complexes
  • Phosphorylation / physiology
  • Protein Stability
  • Proteins / genetics
  • Proteins / metabolism*
  • TOR Serine-Threonine Kinases / genetics
  • TOR Serine-Threonine Kinases / metabolism*

Substances

  • ISCU protein, human
  • Iron-Sulfur Proteins
  • IscU protein, mouse
  • Multiprotein Complexes
  • Proteins
  • Iron
  • TOR Serine-Threonine Kinases
  • Mechanistic Target of Rapamycin Complex 1