title: Disposal of iron by a mutant form of lipocalin 2.
abstract: Iron overload damages many organs. Unfortunately, therapeutic iron chelators also have undesired toxicity and may deliver iron to microbes. Here we show that a mutant form (K3Cys) of endogenous lipocalin 2 (LCN2) is filtered by the kidney but can bypass sites of megalin-dependent recapture, resulting in urinary excretion. Because K3Cys maintains recognition of its cognate ligand, the iron siderophore enterochelin, this protein can capture and transport iron even in the acidic conditions of urine. Mutant LCN2 strips iron from transferrin and citrate, and delivers it into the urine. In addition, it removes iron from iron overloaded mice, including models of acquired (iron-dextran or stored red blood cells) and primary (Hfe-/-) iron overload. In each case, the mutants reduce redox activity typical of non-transferrin-bound iron. In summary, we present a non-toxic strategy for iron chelation and urinary elimination, based on manipulating an endogenous protein:siderophore:iron clearance pathway.
authors: Columbia University, Russ Berrie Medical Science Pavilion, 1150 Saint Nicholas Avenue, Rm 411, New York, New York 10032, USA.
authors: Jonathan
authors: J
authors: Barasch
authors: Columbia University, Russ Berrie Medical Science Pavilion, 1150 Saint Nicholas Avenue, Rm 411, New York, New York 10032, USA.
authors: Maria
authors: M
authors: Hollmen
authors: Columbia University, Russ Berrie Medical Science Pavilion, 1150 Saint Nicholas Avenue, Rm 411, New York, New York 10032, USA.
authors: Rong
authors: R
authors: Deng
authors: Columbia University, Russ Berrie Medical Science Pavilion, 1150 Saint Nicholas Avenue, Rm 411, New York, New York 10032, USA.
authors: Eldad A
authors: EA
authors: Hod
authors: Fred Hutchinson Cancer Research Center, Basic Sciences Division, University of Washington School of Medicine Biochemistry, Immunology, Mail Stop A3-025, Seattle, Washington 98109, USA.
authors: Peter B
authors: PB
authors: Rupert
authors: Lawrence Berkeley National Laboratory, Chemical Sciences Division, BioActinide Chemistry Group, MS 70A-1150, One Cyclotron Road, Berkeley, California 94720, USA.
authors: Rebecca J
authors: RJ
authors: Abergel
authors: Lawrence Berkeley National Laboratory, Chemical Sciences Division, BioActinide Chemistry Group, MS 70A-1150, One Cyclotron Road, Berkeley, California 94720, USA.
authors: Benjamin E
authors: BE
authors: Allred
authors: Columbia University, Russ Berrie Medical Science Pavilion, 1150 Saint Nicholas Avenue, Rm 411, New York, New York 10032, USA.
authors: Katherine
authors: K
authors: Xu
authors: Columbia University, Russ Berrie Medical Science Pavilion, 1150 Saint Nicholas Avenue, Rm 411, New York, New York 10032, USA.
authors: Shaun F
authors: SF
authors: Darrah
authors: Columbia University, Russ Berrie Medical Science Pavilion, 1150 Saint Nicholas Avenue, Rm 411, New York, New York 10032, USA.
authors: Yared
authors: Y
authors: Tekabe
authors: Columbia University, Russ Berrie Medical Science Pavilion, 1150 Saint Nicholas Avenue, Rm 411, New York, New York 10032, USA.
authors: Alan
authors: A
authors: Perlstein
authors: Columbia University, Russ Berrie Medical Science Pavilion, 1150 Saint Nicholas Avenue, Rm 411, New York, New York 10032, USA.
authors: Rebecca
authors: R
authors: Wax
authors: Columbia University, Russ Berrie Medical Science Pavilion, 1150 Saint Nicholas Avenue, Rm 411, New York, New York 10032, USA.
authors: Efrat
authors: E
authors: Bruck
authors: Columbia University, Russ Berrie Medical Science Pavilion, 1150 Saint Nicholas Avenue, Rm 411, New York, New York 10032, USA.
authors: Jacob
authors: J
authors: Stauber
authors: Columbia University, Russ Berrie Medical Science Pavilion, 1150 Saint Nicholas Avenue, Rm 411, New York, New York 10032, USA.
authors: Kaitlyn A
authors: KA
authors: Corbin
authors: Columbia University, Russ Berrie Medical Science Pavilion, 1150 Saint Nicholas Avenue, Rm 411, New York, New York 10032, USA.
authors: Charles
authors: C
authors: Buchen
authors: Columbia University, Russ Berrie Medical Science Pavilion, 1150 Saint Nicholas Avenue, Rm 411, New York, New York 10032, USA.
authors: Vesna
authors: V
authors: Slavkovich
authors: Columbia University, Russ Berrie Medical Science Pavilion, 1150 Saint Nicholas Avenue, Rm 411, New York, New York 10032, USA.
authors: Joseph
authors: J
authors: Graziano
authors: Columbia University, Russ Berrie Medical Science Pavilion, 1150 Saint Nicholas Avenue, Rm 411, New York, New York 10032, USA.
authors: Steven L
authors: SL
authors: Spitalnik
authors: State Key Laboratory of Tea Plant Biology and Utilization, School of Tea and Food Sciences, Anhui Agricultural University, 130 Changjiang West Road, Hefei 230036, China.
authors: Guanhu
authors: G
authors: Bao
authors: Fred Hutchinson Cancer Research Center, Basic Sciences Division, University of Washington School of Medicine Biochemistry, Immunology, Mail Stop A3-025, Seattle, Washington 98109, USA.
authors: Roland K
authors: RK
authors: Strong
authors: Columbia University, Russ Berrie Medical Science Pavilion, 1150 Saint Nicholas Avenue, Rm 411, New York, New York 10032, USA.|Columbia University, New York &Tongji University, School of Life Sciences and Technology, 1239 Siping Road, Shanghai 200092, China.
authors: Andong
authors: A
authors: Qiu
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D006801:Humans; D007249:Inflammation; D007501:Iron / Q000378:metabolism*; D007502:Iron Chelating Agents; D019190:Iron Overload / Q000235:genetics / Q000378:metabolism*; D007668:Kidney / Q000378:metabolism; D008024:Ligands; D000071068:Lipocalin-2 / Q000235:genetics* / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D010084:Oxidation-Reduction; D011485:Protein Binding; D017262:Siderophores; D014168:Transferrin / Q000378:metabolism
chemical_list: D007502:Iron Chelating Agents; C489506:LCN2 protein, human; D008024:Ligands; D000071068:Lipocalin-2; D017262:Siderophores; D014168:Transferrin; C071332:Lcn2 protein, mouse; D007501:Iron