An E3 ligase possessing an iron-responsive hemerythrin domain is a regulator of iron homeostasis

Ameen A. Salahudeen, Joel W. Thompson, Julio C. Ruiz, He Wen Ma, Lisa N. Kinch, Qiming Li, Nick V. Grishin, Richard K. Bruick

Research output: Contribution to journalArticlepeer-review

250 Scopus citations

Abstract

Cellular iron homeostasis is maintained by the coordinate posttranscriptional regulation of genes responsible for iron uptake, release, use, and storage through the actions of the iron regulatory proteins IRP1 and IRP2. However, the manner in which iron levels are sensed to affect IRP2 activity is poorly understood. We found that an E3 ubiquitin ligase complex containing the FBXL5 protein targets IRP2 for proteasomal degradation. The stability of FBXL5 itself was regulated, accumulating under iron- and oxygen-replete conditions and degraded upon iron depletion. FBXL5 contains an iron- and oxygen-binding hemerythrin domain that acted as a ligand-dependent regulatory switch mediating FBXL5's differential stability. These observations suggest a mechanistic link between iron sensing via the FBXL5 hemerythrin domain, IRP2 regulation, and cellular responses to maintain mammalian iron homeostasis.

Original languageEnglish (US)
Pages (from-to)722-726
Number of pages5
JournalScience
Volume326
Issue number5953
DOIs
StatePublished - Oct 30 2009

ASJC Scopus subject areas

  • General

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