Hepcidin: Iron-hormone and anti-microbial peptide

Falzacappa, Maria Vittoria Verga; Muckenthaler, Martina U.

doi:10.1016/j.gene.2005.07.020

Cited by 93 publications

(77 citation statements)

References 47 publications

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“…In patients with juvenile hemochromatosis and in mice lacking hemojuvelin, levels of gene expression of the liver-derived iron-regulating hormone, hepcidin, are reduced (Papanikolaou et al, 2004;Huang et al, 2005;Niederkofler et al, 2005). Hepcidin limits both iron absorption from the duodenum and release of recovered iron by macrophages through binding to the iron export protein, ferroportin, leading to its internalization and degradation (Nemeth et al, 2004), and thus appears to function as a key nodal point in a final common pathway of iron homeostasis (Verga Falzacappa and Muckenthaler, 2005).…”

Section: Introductionmentioning

confidence: 99%

Complex biosynthesis of the muscle-enriched iron regulator RGMc

Kuninger

Kuns-Hashimoto

Kuzmickas

et al. 2006

Journal of Cell Science

120

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The recently discovered repulsive guidance molecule c (RGMc or hemojuvelin) gene encodes a putative glycosylphosphatidylinositol (GPI)-anchored protein that is expressed in striated muscle and in liver. Mutations in this gene have been linked to the severe iron storage disease, juvenile hemochromatosis, although the mechanisms of action of RGMc in iron metabolism are unknown. As a first step toward understanding the molecular physiology of this protein, we studied its biosynthesis, processing and maturation. Production of RGMc occurs as an early and sustained event during skeletal muscle differentiation in culture and is secondary to RGMc gene activation. As assessed by pulse-chase studies and cell-surface labeling experiments, two classes of GPI-anchored and glycosylated RGMc molecules are targeted to the membrane and undergo distinct fates. Full-length RGMc is released from the cell surface and accumulates in extracellular fluid, where its half-life exceeds 24 hours. By contrast, the predominant membrane-associated isoform, a disulfide-linked heterodimer composed of N- and C-terminal fragments, is not found in the extracellular fluid, and is short-lived, as it disappears from the cell surface with a half-life of <3 hours after interruption of protein synthesis. A natural disease-associated RGMc mutant, with valine substituted for glycine at residue 320 (313 in mouse RGMc), does not undergo processing to generate the heterodimeric membrane-linked isoform of RGMc, and is found on the cell surface only as larger protein species. Our results define a series of biosynthetic steps leading to the normal production of different RGMc isoforms in cells, and provide a framework for understanding the biochemical basis of defects in the maturation of RGMc in juvenile hemochromatosis.

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Section: Introductionmentioning

confidence: 99%

Complex biosynthesis of the muscle-enriched iron regulator RGMc

Kuninger

Kuns-Hashimoto

Kuzmickas

et al. 2006

Journal of Cell Science

120

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“…This includes the production of iron-binding proteins, reducing dietary iron assimilation and increasing hepatic production of haemoglobin and hemin scavengers [10]. Hepcidin can directly bind to iron-binding proteins like ferroprotein, which leads to its internalisation and degradation resulting in limited availability of iron for bacterial growth [15,32]. The iron regulatory activity of hepcidin thereby further enhances its antimicrobial activity.…”

Section: Discussionmentioning

confidence: 99%

A Novel Isoform of the Hepatic Antimicrobial Peptide, Hepcidin (Hepc-CB1), from a Deep-Sea Fish, the Spinyjaw Greeneye Chlorophthalmus bicornis (Norman, 1939): Molecular Characterisation and Phylogeny

Chaithanya

Philip

Sathyan

et al. 2012

Probiotics & Antimicro. Prot.

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Hepcidin is cysteine-rich short peptide of innate immune system of fishes, equipped to perform prevention and proliferation of invading pathogens like bacteria and viruses by limiting iron availability and activating intracellular cascades. Hepcidins are diverse in teleost fishes, due to the varied aquatic environments including exposure to pathogens, oxygenation and iron concentration. In the present study, we report a 87-amino acid (aa) preprohepcidin (Hepc-CB1) with a signal peptide of 24 aa, a prodomain of 39 aa and a bioactive mature peptide of 24 aa from the gill mRNA transcripts of the deep-sea fish spinyjaw greeneye, Chlorophthalmus bicornis. Molecular characterisation and phylogenetic analysis categorised the peptide to HAMP2-like group with a mature peptide of 2.53 kDa; a net positive charge (?3) and capacity to form b-hairpin-like structure configured by 8 conserved cysteines. The present work provides new insight into the mass gene duplication events and adaptive evolution of hepcidin isoforms with respect to environmental influences and positive Darwinian selection. This work reports a novel hepcidin isoform under the group HAMP2 from a nonacanthopterygian deep-sea fish, C. bicornis.

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“…In addition, the discovery that microplusin binds copper and iron provides a clue to the role of this protein in the homeostasis of these metals in ticks. In this context, the dual function of hepcidin as an antimicrobial as well as a regulator of systemic iron homeostasis in mice and humans is well known (22).…”

Section: Discussionmentioning

confidence: 99%

Structure and Mode of Action of Microplusin, a Copper II-chelating Antimicrobial Peptide from the Cattle Tick Rhipicephalus (Boophilus) microplus

Silva

Rezende

Rossi

et al. 2009

Journal of Biological Chemistry

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Microplusin, a Rhipicephalus (Boophilus) microplus antimicrobial peptide (AMP) is the first fully characterized member of a new family of cysteine-rich AMPs with histidine-rich regions at the N and C termini. In the tick, microplusin belongs to the arsenal of innate defense molecules active against bacteria and fungi. Here we describe the NMR solution structure of microplusin and demonstrate that the protein binds copper II and iron II. Structured as a single ␣-helical globular domain, microplusin consists of five ␣-helices: ␣1 (residues Gly-9 to Arg-21), ␣2 (residues Glu-27 to Asn-40), ␣3 (residues Arg-44 to Thr-54), ␣4 (residues Leu-57 to Tyr-64), and ␣5 (residues Asn-67 to Cys-80). The N and C termini are disordered. This structure is unlike any other AMP structures described to date. We also used NMR spectroscopy to map the copper binding region on microplusin. Finally, using the Gram-positive bacteria Micrococcus luteus as a model, we studied of mode of action of microplusin. Microplusin has a bacteriostatic effect and does not permeabilize the bacterial membrane. Because microplusin binds metals, we tested whether this was related to its antimicrobial activity. We found that the bacteriostatic effect of microplusin was fully reversed by supplementation of culture media with copper II but not iron II. We also demonstrated that microplusin affects M. luteus respiration, a copper-dependent process. Thus, we conclude that the antibacterial effect of microplusin is due to its ability to bind and sequester copper II.

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Hepcidin: Iron-hormone and anti-microbial peptide

Cited by 93 publications

References 47 publications

Complex biosynthesis of the muscle-enriched iron regulator RGMc

Complex biosynthesis of the muscle-enriched iron regulator RGMc

A Novel Isoform of the Hepatic Antimicrobial Peptide, Hepcidin (Hepc-CB1), from a Deep-Sea Fish, the Spinyjaw Greeneye Chlorophthalmus bicornis (Norman, 1939): Molecular Characterisation and Phylogeny

Structure and Mode of Action of Microplusin, a Copper II-chelating Antimicrobial Peptide from the Cattle Tick Rhipicephalus (Boophilus) microplus

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