title: An E3 ligase possessing an iron-responsive hemerythrin domain is a regulator of iron homeostasis.
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.
authors.affiliation: Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Ameen A
authors.initials: AA
authors.lastname: Salahudeen
authors.forename: Joel W
authors.initials: JW
authors.lastname: Thompson
authors.forename: Julio C
authors.initials: JC
authors.lastname: Ruiz
authors.forename: He-Wen
authors.initials: HW
authors.lastname: Ma
authors.forename: Lisa N
authors.initials: LN
authors.lastname: Kinch
authors.forename: Qiming
authors.initials: Q
authors.lastname: Li
authors.forename: Nick V
authors.initials: NV
authors.lastname: Grishin
authors.forename: Richard K
authors.initials: RK
authors.lastname: Bruick
mesh_terms: D020134:Catalytic Domain; D002460:Cell Line; D044783:F-Box Proteins / Q000737:chemistry / Q000378:metabolism*; D006367:HeLa Cells; D006422:Hemerythrin / Q000378:metabolism*; D006706:Homeostasis; D006801:Humans; D007501:Iron / Q000378:metabolism*; D035942:Iron Regulatory Protein 2 / Q000378:metabolism; D010100:Oxygen / Q000378:metabolism; D017434:Protein Structure, Tertiary; D034741:RNA, Small Interfering; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D043743:Ubiquitin-Protein Ligase Complexes; D044767:Ubiquitin-Protein Ligases / Q000737:chemistry / Q000378:metabolism*
chemical_list: D044783:F-Box Proteins; C521741:FBXL5 protein, human; D006422:Hemerythrin; D034741:RNA, Small Interfering; D011993:Recombinant Fusion Proteins; D007501:Iron; D043743:Ubiquitin-Protein Ligase Complexes; D044767:Ubiquitin-Protein Ligases; C546174:IREB2 protein, human; D035942:Iron Regulatory Protein 2; D010100:Oxygen