Trends in Microbiology
Volume 8, Issue 5, 1 May 2000, Pages 231-237
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Review
The staphylococcal transferrin receptor: a glycolytic enzyme with novel functions

https://doi.org/10.1016/S0966-842X(00)01728-5Get rights and content

Abstract

To obtain iron from the host for growth, staphylococci have evolved sophisticated iron-scavenging systems including siderophores and a cell surface receptor for transferrin, the mammalian iron-transporting glycoprotein. The staphylococcal transferrin receptor has been identified as a member of a newly emerging family of multifunctional, cell-surface-associated glyceraldehyde-3-phosphate dehydrogenases, which not only retain their glycolytic enzyme activities but also bind diverse human serum proteins and possess NAD-ribosylating activity. These multiple functions suggest a potential contribution to virulence far beyond iron acquisition.

Section snippets

Receptor-mediated recognition and uptake of iron from transferrin

Staphylococci are commonly responsible for peritonitis in kidney patients undergoing treatment for renal failure by continuous ambulatory peritoneal dialysis (CAPD). To simulate the in vivo growth environment, Modun et al.10 grew S. aureus and a number of different coagulase-negative staphylococci in human peritoneal dialysate (fluid drained from the abdominal cavity of kidney dialysis patients). This peritoneal dialysate is essentially a plasma ultrafiltrate and contains several human proteins

The staphylococcal transferrin-binding protein is a surface-associated glycolytic enzyme

The staphylococcal transferrin receptor protein (Tpn) was identified by Modun et al.10 as a cell wall protein migrating on SDS-PAGE gels with a mass of ∼42 kDa. Tpn is expressed in vivo in both human and experimental animal models of infection19. Peritoneal dialysates and sera from CAPD patients suffering from staphylococcal peritonitis contain anti-Tpn antibodies, which block transferrin binding19. In S. epidermidis and some S. aureus strains, Tpn expression is regulated by the availability of

A family of GAPDHs with diverse biological functions

GAPDHs have traditionally been considered soluble cytoplasmic enzymes, and although they have been extensively employed as models for protein structure and function, their established role as ‘house-keeping’ genes and gene products has significantly reduced the interest of the scientific community in GAPDHs per se. However, several investigators working on distinct mammalian and microbial cell processes have identified a role for proteins of ∼37–40 kDa that subsequently proved to be GAPDH

How are bacterial GAPDHs targeted to the cell wall?

The multiple functions reported for both staphylococcal Tpn and the streptococcal SDH proteins depend on their location at the cell surface. The evidence for a surface location is provided by cell fractionation studies in which the surface proteins are released by digesting the cell wall with an enzyme such as lysostaphin (for the staphylococci) or mutanolysin (for the streptococci) in a hypertonic solution of a non-metabolizable sugars, in order that cell wall proteins can readily be separated

Internalization of iron released from Tpn-bound transferrin

Although the mechanism by which iron is released from Tpn-bound transferrin has not yet been elucidated, it could depend, as suggested above, on the formation of 1,3-diphosphoglycerate, which can function as an iron-accepting ligand. Whatever the mechanism, to be of value to the bacterial cell, iron released from receptor-bound transferrin must be internalized. Therefore, staphylococci must possess efficient mechanisms for transporting iron across the cytoplasmic membrane. Several

Iron-dependent gene regulation in the staphylococci

The ferric uptake regulator (Fur) is responsible for the iron-dependent transcriptional regulation of genes involved in the biosynthesis and transport of siderophores, in transferrin receptor expression and in the control of certain exotoxin virulence determinants in Gram-negative bacteria34. Fur functions as an iron-responsive repressor, which, in the presence of Fe2+, binds to a consensus sequence termed the Fur box located within the promoter region of target genes. Although Fur homologues

Conclusions

In common with Gram-negative bacteria, the staphylococci have evolved multiple high-affinity iron-scavenging systems based on siderophores and transferrin receptors. Although there is sufficient information to propose a model for the acquisition of transferrin-bound iron by the staphylococci (Fig. 1), much more work is required. As yet, relatively few of the structural or regulatory genes and gene products involved have been characterized, although this will undoubtedly change as more of the S.

Questions for future research

  • What is the relationship between the cytoplasmic form of the staphylococcal GAPDH and the cell-wall-associated form?

  • How is Tpn targeted to the cell wall?

  • What is the nature of the transferrin-binding site on Tpn?

  • What is the relationship between the formation of 1,3 diphosphoglycerate and the release of iron from receptor-bound transferrin?

  • Is the iron released from receptor-bound transferrin internalized via a lipoprotein-dependent ABC transporter?

  • Does the staphylococcal Tpn protein possess

Acknowledgements

Work in this laboratory is supported by grants from the Medical Research Council UK, which are gratefully acknowledged. We thank Dr Alan Cockayne (Institute of Infections and Immunity, University of Nottingham) and Dr Rob Evans (Kings College, University of London) for their helpful comments on the manuscript.

References (39)

  • A.L. Schade

    Significance of serum iron for the growth, biological characteristics and metabolism of Staphylococcus aureus

    Biochem. Z.

    (1963)
  • J.A. Lindsay

    Staphylococcus aureus but not Staphylococcus epidermidis can acquire iron from transferrin

    Microbiology

    (1995)
  • B. Modun

    Receptor-mediated recognition and uptake of iron from human transferrin by Staphylococcus aureus and Staphylococcus epidermidis

    Infect. Immun.

    (1998)
  • H. Drechsel

    Purification and chemical characterization of staphyloferrin B, a hydrophilic siderophore from staphylococci

    Biometals

    (1993)
  • R.J. Courcol

    Siderophore production by Staphylococcus aureus and identification of iron-regulated proteins

    Infect. Immun.

    (1997)
  • Y. Lim

    Iron repressibility of siderophore and transferrin-binding protein in Staphylococcus aureus

    FEMS Microbiol. Letts.

    (1998)
  • J.H. Brock

    Relative availability of transferrin-bound iron and cell-derived iron to aerobactin-producing and enterochelin-producing strains of Escherichia coli and to other microorganisms

    Infect. Immun.

    (1991)
  • J. Tsai

    Loss of transferrin receptor activity in Neisseria meningitidis correlates with inability to use transferrin as an iron source

    Infect. Immun.

    (1988)
  • S.P. Young

    The effect of iron saturation of transferrin on its binding and uptake by rabbit reticulocytes

    Biochem. J.

    (1984)
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