Identification of the receptor scavenging hemopexin-heme complexes

Hvidberg, Vibeke; Maniecki, Maciej Bogdan; Jacobsen, Christian; Højrup, Peter; Møller, Holger Jon; Moestrup, Søren K.

doi:10.1182/blood-2005-03-1185

Cited by 406 publications

(366 citation statements)

References 47 publications

Supporting

Mentioning

355

Contrasting

Unclassified

Order By: Relevance

“…Recently, the low density lipoprotein receptor-related protein was identified as the transmembrane receptor that mediates copper-induced PrP C internalization (44). Low density lipoprotein receptor-related protein also participates in the internalization of the hemin-hemopexin complex resulting in cellular hemin uptake (45). At the moment, it is not clear whether PrP C acts as a receptor for free hemin or interacts with hemin-hemopexin complexes and acts as a co-receptor in compartments such as blood and liver when these complexes are formed.…”

Section: Discussionmentioning

confidence: 99%

Hemin Interactions and Alterations of the Subcellular Localization of Prion Protein

Lee

Raymond

Schoen

et al. 2007

Journal of Biological Chemistry

View full text Add to dashboard Cite

Hemin (iron protoporphyrin IX) is a crucial component of many physiological processes acting either as a prosthetic group or as an intracellular messenger. Some unnatural, synthetic porphyrins have potent anti-scrapie activity and can interact with normal prion protein (PrP C ). These observations raised the possibility that hemin, as a natural porphyrin, is a physiological ligand for PrP C . Accordingly, we evaluated PrP C interactions with hemin. When hemin (3-10 M) was added to the medium of cultured cells, clusters of PrP C formed on the cell surface, and the detergent solubility of PrP C decreased. The addition of hemin also induced PrP C internalization and turnover. The ability of hemin to bind directly to PrP C was demonstrated by hemin-agarose affinity chromatography and UV-visible spectroscopy. Multiple hemin molecules bound primarily to the N-terminal third of PrP C , with reduced binding to PrP C lacking residues 34 -94. These hemin-PrP C interactions suggest that PrP C may participate in hemin homeostasis, sensing, and/or uptake and that hemin might affect PrP C functions.

show abstract

Section: Discussionmentioning

confidence: 99%

Hemin Interactions and Alterations of the Subcellular Localization of Prion Protein

Lee

Raymond

Schoen

et al. 2007

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…However, free heme is highly toxic and can be released at the site of injury by heme proteins including Mb, enzymes such as the cytochromes or catalase, or by oxidation of Hb. In these scenarios, the circulating acute phase protein, hemopexin (Hx) binds to heme and serves as a means for its clearance (68,70,78). In 2005, Hvidberg and colleagues identified the low-density lipoprotein (LDL) receptor-related protein, CD91, as the hemopexin complexed with heme (Hx:heme) complex receptor (70).…”

Section: Role Of Ho-1 In the Mononuclear Phagocyte Systemmentioning

confidence: 99%

“…In these scenarios, the circulating acute phase protein, hemopexin (Hx) binds to heme and serves as a means for its clearance (68,70,78). In 2005, Hvidberg and colleagues identified the low-density lipoprotein (LDL) receptor-related protein, CD91, as the hemopexin complexed with heme (Hx:heme) complex receptor (70). Hx:heme complexes (but not heme alone) undergo receptormediated endocytosis upon binding to CD91, which is followed by recycling of CD91 to the cell membrane, degradation of Hx in the endosome, and delivery of heme to HO-1 (Fig.…”

Section: Role Of Ho-1 In the Mononuclear Phagocyte Systemmentioning

confidence: 99%

The Mononuclear Phagocyte System in Homeostasis and Disease: A Role for Heme Oxygenase-1

Hull

Agarwal

George

2014

Antioxidants & Redox Signaling

View full text Add to dashboard Cite

Significance: Heme oxygenase-1 (HO-1) is a potential therapeutic target in many diseases, especially those mediated by oxidative stress and inflammation. HO-1 expression appears to regulate the homeostatic activity and distribution of mononuclear phagocytes ( MP) in lymphoid tissue under physiological conditions. It also regulates the ability of MP to modulate the inflammatory response to tissue injury. Recent Advances: The induction of HO-1 within MP-particularly macrophages and dendritic cells-modulates the effector functions that they acquire after activation. These effector functions include cytokine production, surface receptor expression, maturation state, and polarization toward a pro-or anti-inflammatory phenotype. The importance of HO-1 in MP is emphasized by their expression of specific receptors that primarily function to ingest heme-containing substrate and deliver it to HO-1. Critical Issues: MP are the first immunological responders to tissue damage. They critically affect the outcome of injury to many organ systems, yet few therapies are currently available to specifically target MP during disease pathogenesis. Elucidation of the role of HO-1 expression in MP may help to direct broadly applicable therapies to clinical use that are based on the immunomodulatory capabilities of HO-1. Future Directions: Unraveling the complexities of HO-1 expression specifically within MP will more completely define how HO-1 provides cytoprotection in vivo. The use of models in which HO-1 expression is specifically modulated in bone marrow-derived cells will allow for a more complete characterization of its immunoregulatory properties.

show abstract

“…The final step of heme biosynthesis occurs in the mitochondria (6). Because free heme is toxic to cells as a result of its potential to generate reactive oxygen species that can cause damage to DNA, proteins, and lipids (3), cells keep intracellularfree heme levels to the minimum (6)(7)(8) and heme homeostasis is one of the most highly regulated processes in mammals (9). Heme insertion into apo-proteins is a key posttranslational event that must take place within this context.…”

mentioning

confidence: 99%

GAPDH regulates cellular heme insertion into inducible nitric oxide synthase

Chakravarti

Aulak

Fox

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

123

146

View full text Add to dashboard Cite

Heme proteins play essential roles in biology, but little is known about heme transport inside mammalian cells or how heme is inserted into soluble proteins. We recently found that nitric oxide (NO) blocks cells from inserting heme into several proteins, including cytochrome P450s, hemoglobin, NO synthases, and catalase. This finding led us to explore the basis for NO inhibition and to identify cytosolic proteins that may be involved, using inducible NO synthase (iNOS) as a model target. Surprisingly, we found that GAPDH plays a key role. GAPDH was associated with iNOS in cells. Pure GAPDH bound tightly to heme or to iNOS in an NO-sensitive manner. GAPDH knockdown inhibited heme insertion into iNOS and a GAPDH mutant with defective heme binding acted as a dominant negative inhibitor of iNOS heme insertion. Exposing cells to NO either from a chemical donor or by iNOS induction caused GAPDH to become S -nitrosylated at Cys152. Expressing a GAPDH C152S mutant in cells or providing a drug to selectively block GAPDH S -nitrosylation both made heme insertion into iNOS resistant to the NO inhibition. We propose that GAPDH delivers heme to iNOS through a process that is regulated by its S -nitrosylation. Our findings may uncover a fundamental step in intracellular heme trafficking, and reveal a mechanism whereby NO can govern the process.

show abstract

Identification of the receptor scavenging hemopexin-heme complexes

Cited by 406 publications

References 47 publications

Hemin Interactions and Alterations of the Subcellular Localization of Prion Protein

Hemin Interactions and Alterations of the Subcellular Localization of Prion Protein

The Mononuclear Phagocyte System in Homeostasis and Disease: A Role for Heme Oxygenase-1

GAPDH regulates cellular heme insertion into inducible nitric oxide synthase

Contact Info

Product

Resources

About