Activation of the HIF Prolyl Hydroxylase by the Iron Chaperones PCBP1 and PCBP2

Nandal, Anjali; Ruiz, Julio C.; Subramanian, Poorna; Ghimire-Rijal, Sudipa; Sinnamon, Ruth Ann; Stemmler, Timothy L.; Bruick, Richard K.; Philpott, Caroline C.

doi:10.1016/j.cmet.2011.08.015

Cited by 186 publications

(162 citation statements)

References 30 publications

Supporting

Mentioning

160

Contrasting

Order By: Relevance

“…Silver staining revealed an additional band (arrow in Figure 8A), which was specifically present in the pull-down from the pig cortex tissue. This band was isolated for mass spectrometry and found to contain Poly(rC)-binding protein 1 (PCBP1), a nuclear RNA-binding protein [35][36][37]. We then performed GST pull-down with an antibody to PCBP1, which confirmed that pig PCBP1, but not mouse PCBP1, bound to hSOD1 ( Figure 8B).…”

Section: Hsod1 Interacts With Pcbp1 In Pig Brainsmentioning

confidence: 83%

“…Using GST pulldown and mass spectrometry, we identified PCBP1 as a partner for binding to hSOD1 in the pig brain, but not in mouse brain. PCBP1 is a nuclear protein and, along with PCBP-2 and hnRNPK, corresponds to the major cellular poly(rC)-binding protein and has widely diversified functions in mRNA binding and stabilization, translational activation or silencing [35,37,50], as well as iron chaperone function [36]. Since most sALS cases harbor cytoplasmic inclusions containing TDP-43, nuclear proteins that are involved in binding DNA and RNA, nuclear dysfunction and abnormal processing of DNA and RNA are thought to play a role in ALS pathogenesis [51].…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Species-dependent neuropathology in transgenic SOD1 pigs

Yang

Wang

Sun³

et al. 2014

Cell Res

View full text Add to dashboard Cite

Mutations in the human copper/zinc superoxide dismutase 1 (hSOD1) gene cause familial amyotrophic lateral sclerosis (ALS). It remains unknown whether large animal models of ALS mimic more pathological events seen in ALS patients via novel mechanisms. Here, we report the generation of transgenic pigs expressing mutant G93A hSOD1 and showing hind limb motor defects, which are germline transmissible, and motor neuron degeneration in dose-and age-dependent manners. Importantly, in the early disease stage, mutant hSOD1 did not form cytoplasmic inclusions, but showed nuclear accumulation and ubiquitinated nuclear aggregates, as seen in some ALS patient brains, but not in transgenic ALS mouse models. Our findings revealed that SOD1 binds PCBP1, a nuclear poly(rC) binding protein, in pig brain, but not in mouse brain, suggesting that the SOD1-PCBP1 interaction accounts for nuclear SOD1 accumulation and that species-specific targets are key to ALS pathology in large mammals and in humans.

show abstract

Section: Hsod1 Interacts With Pcbp1 In Pig Brainsmentioning

confidence: 83%

Section: Discussionmentioning

confidence: 99%

Species-dependent neuropathology in transgenic SOD1 pigs

Yang

Wang

Sun³

et al. 2014

Cell Res

View full text Add to dashboard Cite

show abstract

“…Iron loading mechanisms inside the cells probably reflect those studied in vitro, even though higher level of complexity and regulation may be present; in particular the interaction and loading of ferritins with iron may be enhanced in vivo by iron chaperones such as the PCBPs that can interact with ferritin with nanomolar affinity and may deliver iron directly at the hydrophilic pores (Shi et al 2008;Leidgens et al 2013). This activity is not specific to ferritin since PCBP1 and PCBP2 also facilitate iron delivery to enzymes with mononuclear and dinuclear iron centers, deoxyhypusine hydroxylase and prolyl and asparagyl hydroxylases respectively (Nandal et al 2011;Frey et al 2014) and PCBP2 can mediate cytosolic iron distribution by interacting with the membrane transporters DMT1 and Ferroportin (Yanatori et al 2014). Further studies are needed to understand the role of these ubiquitous RNA/DNA binding proteins in the maintenance of iron homeostasis.…”

Section: Mammalian Ferritin Structurementioning

confidence: 99%

Biology of ferritin in mammals: an update on iron storage, oxidative damage and neurodegeneration

2014

View full text Add to dashboard Cite

Iron is an abundant transition metal that is essential for life, being associated to many enzyme and oxygen carrier proteins involved in a variety of fundamental cellular processes. At the same time the metal is potentially toxic due to its capacity to engage in the catalytic production of noxious reactive oxygen species. The control of iron availability in the cells is largely dependent on ferritins, ubiquitous proteins with storage and detoxification capacity. In mammals, cytosolic ferritins are composed of two types of subunits, the H and the L chain, assembled to form a 24-mer spherical cage. Ferritin is present also in mitochondria, in the form of a complex with 24 identical chains. Even though the proteins have been known for a long time, their study is a very active and interesting field yet. In this review we will focus our attention to mammalian cytosolic and mitochondrial ferritins, describing the most recent advancement regarding their storage and antioxidant function, the effects of their genetic mutations in human pathology, and also the possible involvement in non-iron related activities. We will also discuss recent evidence connecting ferritins and the toxicity of iron in a set of neurodegenerative disorder characterized by focal cerebral siderosis. IntroductionThe adaptation of life to an oxic environment required the development of mechanisms to deal with the transformation of the water soluble ferrous ion (Fe 2+ ) to the insoluble ferric ion (Fe 3+ ) and with the concomitant generation of dangerous reactive oxygen species (ROS). The ferritin molecules represent an important and ancient mean developed by organisms in the three domains of life to safely handle the necessary, yet potentially toxic metal. Their ability to detoxify and store the metal through safe oxidation processes protects the cells from undue iron-dependent redox chemistry, while a controlled release of the metal guarantees its availability for different and essential enzymatic reactions. Storage and detoxification of iron represent the main functions of these molecules, and much work has been done to understand the chemical and molecular details of this

show abstract

“…Recent data indicate that the answer to both questions is yes. PCBP1 and PCBP2 play a role in the metallation of the iron-dependent prolyl hydroxylases (PHDs) that regulate hypoxia-inducible factor (HIF) 1␣ (20). HIF is a heterodimeric transcription factor that activates the expression of genes involved in the response to hypoxia (21)(22)(23).…”

Section: Pcbpsmentioning

confidence: 99%

Coming into View: Eukaryotic Iron Chaperones and Intracellular Iron Delivery

Philpott

2012

Journal of Biological Chemistry

100

View full text Add to dashboard Cite

Eukaryotic cells contain hundreds of metalloproteins, and ensuring that each protein receives the correct metal ion is a critical task for cells. Recent work in budding yeast and mammalian cells has uncovered a system of iron delivery operating in the cytosolic compartment that involves monothiol glutaredoxins, which bind iron in the form of iron-sulfur clusters, and poly(rC)-binding proteins, which bind Fe(II) directly. In yeast cells, cytosolic monothiol glutaredoxins are required for the formation of heme and iron-sulfur clusters and the metallation of some non-heme iron enzymes. Poly(rC)-binding proteins can act as iron chaperones, delivering iron to target non-heme enzymes through direct protein-protein interactions. Although the molecular details have yet to be explored, these proteins, acting independently or together, may represent the basic cellular machinery for intracellular iron delivery.Metalloproteins are very abundant in all types of cells, where they perform a plethora of enzymatic and regulatory functions. A variety of transition metal ions contribute to the metalloproteome of a cell, with iron and zinc being the most abundant (1). Estimates of the number of cellular proteins containing metal ions vary substantially, and evidence from bacteria suggests that many of the proteins that contain metal ions have not yet been annotated as metalloproteins (2). One method of estimating the prevalence of metalloproteins is to examine structural databases. A survey of enzymes for which three-dimensional structures have been determined indicated that 9% contained zinc, 8% iron, 6% manganese (in many cases, the biologically relevant metal is magnesium), and 1% copper (3). A second approach involves the identification of metalloproteins based on the homology of metal-binding domains and metal-binding sites of known metalloproteins to protein sequences derived from sequenced genomes. This type of bioinformatics approach indicates that zinc proteins constitute ϳ10% of the eukaryotic proteome, non-heme iron proteins account for ϳ1% of the proteome, and copper proteins are Ͻ1% of the proteome (4).Given the presence of so many different metalloproteins, the cell faces several obstacles in ensuring that apoproteins receive the correct metal ion. First, although the primary coordination spheres of metal-binding sites can readily exclude ions based on charge, coordination geometry, and polarity, these sites may not have the capacity to discriminate between divalent metal cations and may even bind a non-cognate metal more tightly than the correct one (1). Second, some metal ions, such as iron and copper, are redox-active and, in the presence of oxygen, can catalyze the formation of dangerous reactive oxygen species. Thus, cells must tightly regulate the uptake and distribution of these metals to use them while avoiding the twin toxicities of mismetallation and oxidative damage. One cellular strategy is to maintain the pools of "free" or unliganded metals at exceedingly low levels. This appears to be especially true fo...

show abstract

Activation of the HIF Prolyl Hydroxylase by the Iron Chaperones PCBP1 and PCBP2

Cited by 186 publications

References 30 publications

Species-dependent neuropathology in transgenic SOD1 pigs

Species-dependent neuropathology in transgenic SOD1 pigs

Biology of ferritin in mammals: an update on iron storage, oxidative damage and neurodegeneration

Coming into View: Eukaryotic Iron Chaperones and Intracellular Iron Delivery

Contact Info

Product

Resources

About