An E3 Ligase Possessing an Iron-Responsive Hemerythrin Domain Is a Regulator of Iron Homeostasis

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

doi:10.1126/science.1176326

Cited by 374 publications

(401 citation statements)

References 27 publications

(50 reference statements)

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“…The data presented here are in line with a model where irondependent ubiquitination and degradation of IRP2 requires the activity of FBXL5, which is regulated in an iron and oxygen-dependent manner [10,11]. We speculate that the Fe-O-Fe center of FBXL5 may be amenable to redox control and sensitized by oxidative stress.…”

Section: Discussionsupporting

confidence: 89%

“…1A, lanes 14-18). Taken together, these data suggest that the degradation of IRP2 by iron involves an oxygen-dependent mechanism, in line with the indispensable function of the Fe-O-Fe center in the hemerythrin domain of FBXL5 [10,11]. Conceivably, a threshold of oxygen is necessary for assembly of the Fe-O-Fe center in FBXL5 and IRP2 degradation, and this builds up during prolonged (8 h) exposure of cells to 0.1% O 2 (Fig.…”

Section: Discussionsupporting

confidence: 71%

“…Iron triggers ubiquitination and degradation of IRP2 via the proteasome [8] by a mechanism involving FBXL5, a component of an E3 ubiquitin ligase complex with iron sensing capacity via its hemerythrin domain [10,11]. Hypoxia destabilizes FBXL5 upon loss of its Fe-O-Fe center, which allows accumulation of IRP2.…”

Section: Discussionmentioning

confidence: 99%

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Redox control of iron regulatory protein 2 stability

2011

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Edited by Stuart Ferguson Keywords:Iron metabolism Iron regulatory protein 2 Proteasome Oxidative stress Hypoxia a b s t r a c t Iron regulatory protein 2 (IRP2) is a critical switch for cellular and systemic iron homeostasis. In iron-deficient or hypoxic cells, IRP2 binds to mRNAs containing iron responsive elements (IREs) and regulates their expression. Iron promotes proteasomal degradation of IRP2 via the F-box protein FBXL5. Here, we explored the effects of oxygen and cellular redox status on IRP2 stability. We show that iron-dependent decay of tetracycline-inducible IRP2 proceeds efficiently under mild hypoxic conditions (3% oxygen) but is compromised in severe hypoxia (0.1% oxygen). A treatment of cells with exogenous H 2 O 2 protects IRP2 against iron and increases its IRE-binding activity. IRP2 is also stabilized during menadione-induced oxidative stress. These data demonstrate that the degradation of IRP2 in iron-replete cells is not only oxygen-dependent but also sensitive to redox perturbations.

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Section: Discussionsupporting

confidence: 89%

Section: Discussionsupporting

confidence: 71%

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Redox control of iron regulatory protein 2 stability

2011

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“…Simultaneously, it represses translation from ferritin mRNA ensuring that iron taken in by the cell is available for use. IRP2 is regulated by iron-dependent ubiquitination and proteasomal degradation (Salahudeen et al 2009 ;Vashisht et al 2009). In the bloodstream, iron levels are controlled principally by macrophages.…”

Section: Iron Uptake and Transport In The Hostmentioning

confidence: 99%

Iron metabolism in trypanosomatids, and its crucial role in infection

Taylor

Kelly

2010

Parasitology

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Iron is almost ubiquitous in living organisms due to the utility of its redox chemistry. It is also dangerous as it can catalyse the formation of reactive free radicals -a classical double-edged sword. In this review, we examine the uptake and usage of iron by trypanosomatids and discuss how modulation of host iron metabolism plays an important role in the protective response. Trypanosomatids require iron for crucial processes including DNA replication, antioxidant defence, mitochondrial respiration, synthesis of the modified base J and, in African trypanosomes, the alternative oxidase. The source of iron varies between species. Bloodstream-form African trypanosomes acquire iron from their host by uptake of transferrin, and Leishmania amazonensis expresses a ZIP family cation transporter in the plasma membrane. In other trypanosomatids, iron uptake has been poorly characterized. Iron-withholding responses by the host can be a major determinant of disease outcome. Their role in trypanosomatid infections is becoming apparent. For example, the cytosolic sequestration properties of NRAMP1, confer resistance against leishmaniasis. Conversely, cytoplasmic sequestration of iron may be favourable rather than detrimental to Trypanosoma cruzi. The central role of iron in both parasite metabolism and the host response is attracting interest as a possible point of therapeutic intervention.

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“…FBXL5 contains a single HHE domain near the N terminus of the protein and assembles into the SKP1-CUL1-F-box-protein [(SCF) FBXL5 ] SCF FBXL5 E3 ligase complex that interacts with iron homeostasis proteins, facilitating their ubiquitin-mediated degradation (Salahudeen et al, 2009;Vashisht et al, 2009). In the absence of iron, conformational changes in FBXL5's HHE domain lead to the degradation of FBXL5 and a subsequent increase in overall iron uptake and metabolism (Salahudeen et al, 2009;Ruiz et al, 2013). Deletion of the FBXL5 HHE domain leads to constitutive accumulation of the truncated protein, while iron and oxygen binding to the HHE domain cause increased FBXL5 protein accumulation (Salahudeen et al, 2009).…”

Section: Hhe Domains Bind Iron and Affect Bts Protein Stabilitymentioning

confidence: 99%

Iron-Binding E3 Ligase Mediates Iron Response in Plants by Targeting Basic Helix-Loop-Helix Transcription Factors

et al. 2014

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Iron uptake and metabolism are tightly regulated in both plants and animals. In Arabidopsis (Arabidopsis thaliana), BRUTUS (BTS), which contains three hemerythrin (HHE) domains and a Really Interesting New Gene (RING) domain, interacts with basic helix-loop-helix transcription factors that are capable of forming heterodimers with POPEYE (PYE), a positive regulator of the iron deficiency response. BTS has been shown to have E3 ligase capacity and to play a role in root growth, rhizosphere acidification, and iron reductase activity in response to iron deprivation. To further characterize the function of this protein, we examined the expression pattern of recombinant ProBTS::b-GLUCURONIDASE and found that it is expressed in developing embryos and other reproductive tissues, corresponding with its apparent role in reproductive growth and development. Our findings also indicate that the interactions between BTS and PYE-like (PYEL) basic helix-loop-helix transcription factors occur within the nucleus and are dependent on the presence of the RING domain. We provide evidence that BTS facilitates 26S proteasome-mediated degradation of PYEL proteins in the absence of iron. We also determined that, upon binding iron at the HHE domains, BTS is destabilized and that this destabilization relies on specific residues within the HHE domains. This study reveals an important and unique mechanism for plant iron homeostasis whereby an E3 ubiquitin ligase may posttranslationally control components of the transcriptional regulatory network involved in the iron deficiency response.

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An E3 Ligase Possessing an Iron-Responsive Hemerythrin Domain Is a Regulator of Iron Homeostasis

Cited by 374 publications

References 27 publications

Redox control of iron regulatory protein 2 stability

Redox control of iron regulatory protein 2 stability

Iron metabolism in trypanosomatids, and its crucial role in infection

Iron-Binding E3 Ligase Mediates Iron Response in Plants by Targeting Basic Helix-Loop-Helix Transcription Factors

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