Human CIA2A-FAM96A and CIA2B-FAM96B integrate iron homeostasis and maturation of different subsets of cytosolic-nuclear iron-sulfur proteins

Cell Metab. 2013 Aug 6;18(2):187-98. doi: 10.1016/j.cmet.2013.06.015. Epub 2013 Jul 25.

Abstract

Numerous cytosolic and nuclear proteins involved in metabolism, DNA maintenance, protein translation, or iron homeostasis depend on iron-sulfur (Fe/S) cofactors, yet their assembly is poorly defined. Here, we identify and characterize human CIA2A (FAM96A), CIA2B (FAM96B), and CIA1 (CIAO1) as components of the cytosolic Fe/S protein assembly (CIA) machinery. CIA1 associates with either CIA2A or CIA2B and the CIA-targeting factor MMS19. The CIA2B-CIA1-MMS19 complex binds to and facilitates assembly of most cytosolic-nuclear Fe/S proteins. In contrast, CIA2A specifically matures iron regulatory protein 1 (IRP1), which is critical for cellular iron homeostasis. Surprisingly, a second layer of iron regulation involves the stabilization of IRP2 by CIA2A binding or upon depletion of CIA2B or MMS19, even though IRP2 lacks an Fe/S cluster. In summary, CIA2B-CIA1-MMS19 and CIA2A-CIA1 assist different branches of Fe/S protein assembly and intimately link this process to cellular iron regulation via IRP1 Fe/S cluster maturation and IRP2 stabilization.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism*
  • Cell Line, Tumor
  • Glycerol-3-Phosphate O-Acyltransferase / metabolism
  • HeLa Cells
  • Homeostasis
  • Humans
  • Iron / metabolism*
  • Iron Regulatory Protein 1 / metabolism
  • Iron Regulatory Protein 2 / metabolism
  • Iron-Sulfur Proteins / biosynthesis*
  • Iron-Sulfur Proteins / metabolism
  • Metallochaperones / genetics
  • Metallochaperones / metabolism*
  • Metalloproteins
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism*
  • Protein Binding
  • RNA Interference
  • RNA, Small Interfering
  • Transcription Factors / metabolism

Substances

  • CIAO1 protein, human
  • CIAO2A protein, human
  • CIAO2B protein, human
  • Carrier Proteins
  • Iron-Sulfur Proteins
  • MMS19 protein, human
  • Metallochaperones
  • Metalloproteins
  • Nuclear Proteins
  • RNA, Small Interfering
  • Transcription Factors
  • Iron
  • Glycerol-3-Phosphate O-Acyltransferase
  • IRP1 protein, human
  • IRP2 protein, human
  • Iron Regulatory Protein 1
  • Iron Regulatory Protein 2