Hepcidin-induced internalization of ferroportin requires binding and cooperative interaction with Jak2

Domenico, Ivana De; Lo, Eric; Kaplan, Jerry

doi:10.1073/pnas.0900453106

Cited by 126 publications

(118 citation statements)

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“…However, it has been shown recently that the hepcidin-FPN interaction leads to activation of the Jak2 kinase (40). This study implicated Jak2-dependent phosphorylation of FPN in downregulation of the receptor, but it is also possible that downstream signals activated by Jak2 could influence gene expression and, therefore, that deficiency of such signals could contribute to the abnormal cytokine production by macrophages from Hfe KO mice.…”

Section: Figurementioning

confidence: 82%

Selective modulation of TLR4-activated inflammatory responses by altered iron homeostasis in mice

Wang¹,

Harrington²,

Trebicka³

et al. 2009

J. Clin. Invest.

117

159

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Mice deficient in the hemochromatosis gene, Hfe, have attenuated inflammatory responses to Salmonella infection associated with decreased macrophage TNF-α and IL-6 biosynthesis after exposure to LPS. In this study, we show that the abnormal cytokine production is related to impaired TLR4 signaling. Despite their abnormal response to LPS, Hfe KO macrophages produced amounts of TNF-α similar to those in WT cells after TLR2 stimulation. Consistent with this finding, LPS-induced activation of Mal/MyD88-dependent events was normal in the mutant macrophages. However, LPS-induced IFN-β expression, a TRAM/TRIF-dependent response activated by TLR4, was reduced by Hfe deficiency. This reduction could be replicated in WT macrophages with the use of iron chelators. In contrast, TLR3-activated expression of IFN-β, a TRIF-dependent response, was normal in Hfe KO macrophages and was unaffected by iron chelation. Our data suggest that low intracellular iron selectively impairs signaling via the TLR4/TRAM/TRIF pathway proximal to TRIF and results in reduced LPS-induced cytokine expression. Furthermore, by mimicking the altered iron metabolism associated with Hfe deficiency, we found that 3 different inhibitors of hepcidin attenuated Salmonella-induced and noninfectious enterocolitis. Thus, manipulation of iron homeostasis could represent a new therapeutic approach to controlling inflammation.

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Section: Figurementioning

confidence: 82%

Selective modulation of TLR4-activated inflammatory responses by altered iron homeostasis in mice

Wang¹,

Harrington²,

Trebicka³

et al. 2009

J. Clin. Invest.

117

159

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“…La Fpn tiene la propiedad de funcionar como proteína monomérica o dimérica (11,54,57,59). En los dominios citoplasmáticos de la proteína ocurre la fosforilación y la ubiquitinación, procesos necesarios para la degradación de la proteína por la hepcidina (Hpc) (54,(58)(59)(60)(61)(62). En el humano, la Fpn se sintetiza en la placenta, el hígado, el bazo, el corazón, los riñones, en la membrana basolateral del enterocito y en el citosol de las células del sistema reticuloendotelial (9,28,64).…”

Section: El Receptor 2 De Transferrina (Tfr2)unclassified

“…La Fpn se comporta como un receptor de la Hpc; para formar el complejo Fpn-Hpc la Fpn debe ser fosforilada, lo que induce a la internalización, ubiquitinación y posterior degradación de la Fpn, interrumpiendo el flujo de hierro a la circulación (57)(58)(59)(60)(61)63,(66)(67)(68)(69). En cultivos celulares de ratón, se describió que al disminuir las concentraciones plasmáticas de hierro, también disminuye la sínte-sis de Hpc, hecho que permite el incremento de la Fpn y la salida de hierro a la circulación (57,60).…”

Section: El Receptor 2 De Transferrina (Tfr2)unclassified

Proteínas relacionadas con el metabolismo del hierro corporal

Corrales-Agudelo¹,

Sosa

Herrera

2017

Perspect Nutr Humana

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Como citar este artículo: Corrales-Agudelo V, Parra-Sosa BE, Burgos-Herrera LC. Proteínas relacionadas con el metabolismo del hierro corporal. Perspect Nutr Humana. 2016;18:95-116. DOI:10.17533/udea.penh.v18n1a08 Proteínas relacionadas con el metabolismo del hierro corporal ResumenAntecedentes: el hierro es uno de los minerales más estudiados; existe amplia información en cuanto a su metabolismo, función, interacciones y regulación; sin embargo, los estudios y análisis realizados se basan en proteínas específicas y pocos integran, en un solo texto, las características de estas moléculas relacionadas con el metabolismo del hierro corporal. Objetivo: profundizar en los aspectos moleculares, metabólicos y de modulación de las proteínas que participan en la homeostasis del hierro y en sus interacciones. Materiales y métodos: se hizo una búsqueda sistemática de información en bases de datos científicas de artículos sobre el tema, publicados entre 2006 y 2016. Resultados: la homeostasis del hierro corporal, es un proceso complejo y altamente regulado por diferentes moléculas que participan de manera integrada en su metabolismo; en los últimos años han surgido nuevas proteínas, algunas de ellas participan en el transporte de otros nutrientes y se les ha encontrado relación con el control humoral y celular del hierro; además, involucran la participación de varios órganos, tejidos y sistemas. Esta revisión incluye proteínas encargadas de facilitar el aprovechamiento biológico del nutriente, así como aquellas que protegen a las células de toxicidad por exceso de este mineral.Palabras clave: hierro, proteínas de unión al hierro, expresión génica, oxidación-reducción, homeostasis, deficiencia de hierro. Proteínas del metabolismo del hierro 96Vol. 18, N° 1, enero-junio de 2016Proteins associated with the metabolism of total body iron Abstract Background: Iron is an essential nutrient well studied for its role in human health, and much evidence exists regarding its metabolism, functions, interactions, and regulations. However, studies and analyses that have been done are often based on specific proteins and few integrate into a single text the characteristics of multiple proteins related to total body iron metabolism. Objective: Explore in-depth the molecular, metabolic, and modulation aspects of proteins that participate in iron homeostasis and related interactions. Materials and methods: A literature review was completed using scientific databases in conjunction with a search for related scientific articles published between 2006 and 2016. Results: Homeostasis of total body iron stores is a complex process that is highly regulated by various molecules that participate in an integrated manner in iron metabolism. In recent years, new proteins have been discovered regarding the humoral and cellular control of iron, some of which are also involved in the transport of other nutrients. Additionally, these proteins involve participation from various organs, tissues, and systems. This review includes proteins responsible for ...

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“…If total body iron is high, hepatic synthesis of hepcidin increases. Binding of hepcidin to ferroportin in its exterior segment causes upregulation of Janus kinase 2 [6,7]. Activation of Janus kinase 2 results in internalization, ubiquitination and degradation of ferroportin, which results in decreased iron transfer to blood.…”

Section: Transport Of Iron In Plasmamentioning

confidence: 99%

Iron transport: From enterocyte to mitochondria

Özbek¹

2010

Turk J Hematol

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Transport of iron to tissues is of vital importance. Remarkable advances have been made concerning the mechanisms involving iron metabolism after its absorption. Studies assessing cellular and mitochondrial iron metabolism have resulted in interesting findings. This review highlights the recent advances in the mechanisms involving transport and delivery of iron to tissues, cellular and mitochondrial iron metabolism, iron-related molecules, and mitochondrial disorders. (Turk J Hematol 2010; 27: 137-46) Key words: Iron, iron transport, mitochondria, mitochondrial iron Received: February 8, 2010 Accepted: April 6, 2010 ÖzetDemirin dokulara taşınması yaşamsal önem taşır. Demirin emiliminden sonraki metabolizmasıyla ilgili büyük ilerlemeler kaydedilmiştir. Selüler ve mitokondriyal demir metabolizmasıyla ilgili araştırmalar ilginç sonuçlar vermektedir. Bu derleme demirin dokulara taşınması, verilmesi, hücresel ve mitokondriyal demir metabolizması, demirle ilişkili moleküller ve mitokondriyal hastalıklarla ilgili yeni gelişme-leri vurgulamaktadır. (Turk J Hematol 2010; 27: 137-46) Anahtar kelimeler: Demir, demir taşınımı, mitokondri, mitokondriyal demir Geliş tarihi: 8 Şubat 2010 Kabul tarihi: 6 Nisan 2010A current theme in the field of hematology as well as in other disciplines is the molecular mechanisms concerning iron metabolism. Mechanisms involving absorption of iron by enterocytes has been reviewed elsewhere [1][2][3]. In this review, delivery of iron to tissues, mechanisms concerning cellular and mitochondrial iron metabolism, iron-related molecules, and mitochondrial disorders are presented (Table 1). Transport of iron in plasmaBinding to transferrin (Tf) is the first step in iron transport. Tf has high affinity for ferric iron; therefore, the oxidation of ferrous (Fe +2 ) to the ferric (Fe +3 ) form by hephaestin is an essential step for transport. Hephaestin is a ceruloplasmin homolog, and colocalizes with ferroportin at the basolateral membrane of enterocytes. The role of hephaestin in iron absorption was first shown in the sla (sex-

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Hepcidin-induced internalization of ferroportin requires binding and cooperative interaction with Jak2

Cited by 126 publications

References 30 publications

Selective modulation of TLR4-activated inflammatory responses by altered iron homeostasis in mice

Selective modulation of TLR4-activated inflammatory responses by altered iron homeostasis in mice

Proteínas relacionadas con el metabolismo del hierro corporal

Iron transport: From enterocyte to mitochondria

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