Control of Iron Homeostasis by an Iron-Regulated Ubiquitin Ligase

Vashisht, Ajay A.; Zumbrennen, Kimberly B.; Huang, Xinhua; Powers, David N.; Durazo, Armando; Sun, Dahui; Bhaskaran, Nimesh; Persson, Anja Bondke; Uhlén, Mathias; Sangfelt, Olle; Spruck, Charles; Leibold, Elizabeth A.; Wohlschlegel, James A.

doi:10.1126/science.1176333

Cited by 374 publications

(410 citation statements)

References 25 publications

Supporting

Mentioning

388

Contrasting

Unclassified

Order By: Relevance

“…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: 70%

“…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%

“…3A, compare lanes 1-4 with 5-7). This effect persisted even in the presence of excess (2.5 mM) ascorbate (lanes [11][12][13], that is known to promote IRP2 turnover (lanes 1-7 and [16]). We next examined the effects of ascorbate on other known IRP2 stabilizers.…”

Section: Effects Of Menadione and Ascorbate On Irp2 Stabilitymentioning

confidence: 99%

See 3 more Smart Citations

Redox control of iron regulatory protein 2 stability

2011

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionsupporting

confidence: 89%

Section: Discussionsupporting

confidence: 70%

Section: Discussionmentioning

confidence: 99%

Section: Effects Of Menadione and Ascorbate On Irp2 Stabilitymentioning

confidence: 99%

See 2 more Smart Citations

Redox control of iron regulatory protein 2 stability

2011

View full text Add to dashboard Cite

show abstract

“…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

View full text Add to dashboard Cite

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.

show abstract

Cellular and Systemic Iron Homeostasis

Crichton

2016

Iron Metabolism

View full text Add to dashboard Cite

Control of Iron Homeostasis by an Iron-Regulated Ubiquitin Ligase

Cited by 374 publications

References 25 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

Cellular and Systemic Iron Homeostasis

Contact Info

Product

Resources

About