Article
- The EMBO Journal (2006) 25, 544 - 553
- doi:10.1038/sj.emboj.7600954
Published online: 19 January 2006
Subject Categories:
Iron-responsive degradation of iron-regulatory protein 1 does not require the Fe–S cluster
Stephen L Clarke1,a, Aparna Vasanthakumar1, Sheila A Anderson1, Corinne Pondarré2, Cheryl M Koh1, Kathryn M Deck1, Joseph S Pitula1, Charles J Epstein3, Mark D Fleming2 and Richard S Eisenstein1
- Department of Nutritional Sciences, University of Wisconsin, Madison, WI, USA
- Department of Pathology, Children's Hospital and Harvard Medical School, Boston, MA, USA
- Department of Pediatrics and Center for Human Genetics, University of California, San Francisco, CA, USA
Correspondence to:
Richard S Eisenstein, Department of Nutritional Sciences, University of Wisconsin-Madison, 1415 Linden Drive, Madison, WI 53706, USA. Tel.: +1 608 262 5830; Fax: +1 608 262 5860; E-mail: eisenste@nutrisci.wisc.edu
aPresent address: Department of Physiology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390-8854, USA
Received 4 March 2005; Accepted 19 December 2005
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.
Keywords:
- Fe–S protein,
- iron homeostasis,
- iron-regulatory protein 1,
- phosphorylation,
- protein degradation
MORE ARTICLES LIKE THIS
These links to content published by NPG are automatically generated
REVIEWS
Pathogenesis of parkinson's disease: dopamine, vesicles and α-synuclein
Nature Reviews Neuroscience Review (01 Dec 2002)
The role of iron regulatory proteins in mammalian iron homeostasis and disease
Nature Chemical Biology Perspective (01 Aug 2006)
Heme and Iron Metabolism: Role in Cerebral Hemorrhage
Journal of Cerebral Blood Flow & Metabolism Review
RESEARCH
The EMBO Journal Article (28 Jan 2004)
Identification of RNA-binding surfaces in iron regulatory protein-1
The EMBO Journal Article (01 Nov 1999)
