Iron-responsive degradation of iron-regulatory protein 1 does not require the Fe-S cluster

EMBO J. 2006 Feb 8;25(3):544-53. doi: 10.1038/sj.emboj.7600954. Epub 2006 Jan 19.

Abstract

The generally accepted role of iron-regulatory protein 1 (IRP1) in orchestrating the fate of iron-regulated mRNAs depends on the interconversion of its cytosolic aconitase and RNA-binding forms through assembly/disassembly of its Fe-S cluster, without altering protein abundance. Here, we show that IRP1 protein abundance can be iron-regulated. Modulation of IRP1 abundance by iron did not require assembly of the Fe-S cluster, since a mutant with all cluster-ligating cysteines mutated to serine underwent iron-induced protein degradation. Phosphorylation of IRP1 at S138 favored the RNA-binding form and promoted iron-dependent degradation. However, phosphorylation at S138 was not required for degradation. Further, degradation of an S138 phosphomimetic mutant was not blocked by mutation of cluster-ligating cysteines. These findings were confirmed in mouse models with genetic defects in cytosolic Fe-S cluster assembly/disassembly. IRP1 RNA-binding activity was primarily regulated by IRP1 degradation in these animals. Our results reveal a mechanism for regulating IRP1 action relevant to the control of iron homeostasis during cell proliferation, inflammation, and in response to diseases altering cytosolic Fe-S cluster assembly or disassembly.

Publication types

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

MeSH terms

  • Animals
  • Cell Line
  • Hemin / metabolism
  • Humans
  • Iron / physiology*
  • Iron Regulatory Protein 1 / genetics
  • Iron Regulatory Protein 1 / metabolism*
  • Mice
  • Mice, Knockout
  • Mutation
  • Phosphorylation
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • RNA-Binding Proteins / genetics
  • RNA-Binding Proteins / metabolism
  • Serine / metabolism

Substances

  • RNA, Messenger
  • RNA-Binding Proteins
  • Serine
  • Hemin
  • Iron
  • Iron Regulatory Protein 1