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Emergence of the acute-phase protein hemopexin in jawed vertebrates

Department of Microbiology & Immunology, University of Maryland School of Medicine, 655 West Baltimore Street, Baltimore, MD 21201, USA.
Molecular Immunology (Impact Factor: 3). 09/2010; 48(1-3):147-52. DOI: 10.1016/j.molimm.2010.08.015
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ABSTRACT When released from damaged erythrocytes free heme not only provides a source of iron for invading bacteria but also highly toxic due to its ability to catalyze free radical formation. Hemopexin (Hx) binds free heme with very high-affinity and thus protects against heme toxicity, sequesters heme from pathogens, and helps conserve valuable iron. Hx is also an acute-phase serum protein (APP), whose expression is induced by inflammation. To date Hx has been identified as far back in phylogeny as bony fish where it is called warm-temperature acclimation-related 65 kDa protein (WAP65), as serum protein levels are increased at elevated environmental temperatures as well as by infection. During analysis of nurse shark (Ginglymostoma cirratum) plasma we isolated a Ni(2+)-binding serum glycoprotein and characterized it as the APP Hx. We subsequently cloned Hx from nurse shark and another cartilaginous fish species, the little skate Leucoraja erinacea. Functional analysis showed shark Hx, like that of mammals, binds heme but is found at unusually high levels in normal shark serum. As an Hx orthologue could not be found in the genomes of jawless vertebrates or lower deuterostomes it appears to have arisen just prior to the emergence of jawed vertebrates, coincident with the second round of genome-wide duplication and the appearance of tetrameric hemoglobin (Hb).

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    • "Moreover, a SAA counterpart identified from common carp was found to elevate its expression at mRNA level, in response to a turpentine oil treatment in inflammatory leukocytes (Fujiki et al., 2000). Hemopexin was identified as an emerging APP from a cartilaginous fish, nurse shark in a previous study, confirming its heme binding properties (Dooley et al., 2010). Recently, we identified two putative APPs; SAA and Hp from black rockfish, and found that the expression levels of those two genes were markedly induced under a pathogenic stress (Jayasinghe et al., 2015). "
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    ABSTRACT: The basic function of transferrin is to bind iron (III) ions in the medium and to deliver them to the locations where they are required for metabolic processes. It also takes part in the host immune defense mainly via its ability to bind to iron (III) ions. Hence, transferrin is also identified as an important acutephase protein in host immunity. Abalones are major shellfish aquaculture crops that are susceptible to a range of marine microbial infections. Since transferrin is known to be a major player in innate immunity, in the present study we sought to identify, and molecularly and functionally characterize a transferrinlike gene from disk abalone (Haliotis discus discus) named as AbTrf. AbTrf consisted of a 2187-bp open reading frame (ORF) which encodes a 728 amino acid (aa) protein. The putative amino acid sequence of AbTrf harbored N- and C-terminal transferrin-like domains, active sites for iron binding, and conserved cysteine residues. A constitutive tissue specific AbTrf expression pattern was detected by qPCR in abalones where mantle and muscle showed high AbTrf expression levels. Three immune challenge experiments were conducted using Vibrio parahaemolyticus, Listeria monocytogenes and LPS as stimuli and, subsequently, AbTrf mRNA expression levels were quantified in gill and hemocytes in a time-course manner. The mRNA expression was greatly induced in both tissues in response to both challenges. Evidencing the functional property of transferrins, recombinant AbTrf N-terminal domain (AbTrf-N) showed dose-dependent iron (III) binding activity detected by chrome azurol S (CAS) assay system. Moreover, recombinant AbTrf-N could significantly inhibit the growth of iron-dependent bacterium, Escherichia coli in a dose-dependent manner. However, AbTrf-N was unable to show any detectable bacteriostatic activity against iron-independent bacterium Lactobacillus plantarum (L. plantarum) even at its highest concentration. Collectively, our results suggest that AbTrf might play a significant role in the host innate immunity, possibly by withholding iron from pathogens.
    Developmental & Comparative Immunology 11/2015; 53(1):222-233. DOI:10.1016/j.dci.2015.07.013 · 3.71 Impact Factor
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    • "Moreover, a SAA counterpart identified from common carp was found to elevate its expression at mRNA level, in response to a turpentine oil treatment in inflammatory leukocytes (Fujiki et al., 2000). Hemopexin was identified as an emerging APP from a cartilaginous fish, nurse shark in a previous study, confirming its heme binding properties (Dooley et al., 2010). Recently, we identified two putative APPs; SAA and Hp from black rockfish, and found that the expression levels of those two genes were markedly induced under a pathogenic stress (Jayasinghe et al., 2015). "
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    ABSTRACT: Pentraxins are a family of evolutionary conserved proteins that contains two main members, namely c-reactive proteins (CRPs) and serum amyloid P (SAP), which are involved in acute phase responses in animals. In this study, a cDNA sequence of a CRP-like molecule was identified from a previously constructed black rockfish cDNA database (RfCRP) and subsequently characterized at its molecular level. The complete coding region of RfCRP is 672 bp in length, and encodes a protein containing 224 amino acids with a predicted molecular mass of 25.19 kDa. Analysis of its derived amino acid sequence enabled typical features of pentraxin family members to be identified, including the pentraxin family signature in RfCRP. Results from multiple sequence alignment suggest the conservation of functionally important residues in RfCRP. According to the phylogenetic reconstruction that was generated using different pentraxin counterparts from different taxa, RfCRP shares a common vertebrate ancestral origin and most closely clusters with marine teleostan CRP. Furthermore, recombinant RfCRP demonstrated Ca(2+)-dependent agglutination activity against Escherichia coli, which could be completely inhibited in the presence of carbohydrate based ligands. Moreover, recombinant RfCRP also exhibited anti-bacterial activity against both E. coli and Streptococcus iniae. In addition, qPCR analysis indicated that RfCRP is ubiquitously expressed in physiologically important tissues, with pronounced expression in the spleen. After healthy fish were treated with polysaccharides or live S. iniae, basal expression of RfCRP was significantly upregulated in spleen and head kidney tissues. Collectively, our results suggest that RfCRP may be important in host anti-bacterial defense, and it might potentially participate in the acute phase of infection. Copyright © 2015. Published by Elsevier Ltd.
    Developmental and comparative immunology 07/2015; 53(1). DOI:10.1016/j.dci.2015.07.007 · 3.71 Impact Factor
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    ABSTRACT: Hemopexin is an acute-phase plasma glycoprotein, produced mainly by the liver and released into plasma, where it binds heme with high affinity. Other sites of hemopexin synthesis are the nervous system, skeletal muscle, retina, and kidney. The only known receptor for the heme-hemopexin complex is the scavenger receptor, LDL receptor-related protein (LRP)1, which is expressed in most cell types, thus indicating multiple sites of heme-hemopexin complex recovery. The better-characterized function of hemopexin is heme scavenging at the systemic level, consisting of the transport of heme to the liver, where it is catabolyzed or used for the synthesis of hemoproteins or exported to bile canaliculi. This is important both in physiologic heme management for heme-iron recycling and in pathologic conditions associated with intravascular hemolysis to prevent the prooxidant and proinflammatory effects of heme. Other than scavenging heme, the heme-hemopexin complex has been shown to be able to activate signaling pathways, thus promoting cell survival, and to modulate gene expression. In this review, the importance of heme scavenging by hemopexin, as well as the other emerging functions of this protein, are discussed.
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