The Staphylococcus aureus Protein IsdH Inhibits Host Hemoglobin Scavenging to Promote Heme Acquisition by the Pathogen

Kirstine Lindhardt Saederup; Kristian Stødkilde-Jørgensen; Jonas Heilskov Graversen; Claire F. Dickson; Anders Etzerodt; Soren Werner Karlskov Hansen; Angela Fago; David Gell; Christian Brix Folsted Andersen; Soren Kragh Moestrup

doi:10.1074/jbc.M116.755934

The Staphylococcus aureus Protein IsdH Inhibits Host Hemoglobin Scavenging to Promote Heme Acquisition by the Pathogen

Kirstine Lindhardt Saederup, Kristian Stødkilde-Jørgensen, Jonas Heilskov Graversen, Claire F. Dickson, Anders Etzerodt, Soren Werner Karlskov Hansen, Angela Fago, David Gell, Christian Brix Folsted Andersen, Soren Kragh Moestrup^*

^*Corresponding author af dette arbejde

Publikation: Bidrag til tidsskrift/Konferencebidrag i tidsskrift /Bidrag til avis › Tidsskriftartikel › Forskning › peer review

24 Citationer (Scopus)

Abstract

Hemolysis is a complication in septic infections with Staphylococcus aureus, which utilizes the released Hb as an iron source. S. aureus can acquire heme in vitro from hemoglobin (Hb) by a heme-sequestering mechanism that involves proteins from the S. aureus iron-regulated surface determinant (Isd) system. However, the host has its own mechanism to recapture the free Hb via haptoglobin (Hp) binding and uptake of Hb-Hp by the CD163 receptor in macrophages. It has so far remained unclear how the Isd system competes with this host iron recycling system in situ to obtain the important nutrient. By binding and uptake studies, we now show that the IsdH protein, which serves as an Hb receptor in the Isd system, directly interferes with the CD163-mediated clearance by binding the Hb-Hp complex and inhibiting CD163 recognition. Analysis of truncated IsdH variants including one or more of three near iron transporter domains, IsdH(N1), IsdH(N2), and IsdH(N3), revealed that Hb binding of IsdH(N1) and IsdH(N2) accounted for the high affinity for Hb-Hp complexes. The third near iron transporter domain, IsdH(N3), exhibited redox-dependent heme extraction, when Hb in the Hb-Hp complex was in the oxidized met form but not in the reduced oxy form. IsdB, the other S. aureus Hb receptor, failed to extract heme from Hb-Hp, and it was a poor competitor for Hb-Hp binding to CD163. This indicates that Hb recognition by IsdH, but not by IsdB, sterically inhibits the receptor recognition of Hb-Hp. This function of IsdH may have an overall stimulatory effect on S. aureus heme acquisition and growth.

Originalsprog	Engelsk
Tidsskrift	Journal of Biological Chemistry
Vol/bind	291
Nummer	46
Sider (fra-til)	23989-23998
Antal sider	10
ISSN	0021-9258
DOI	https://doi.org/10.1074/jbc.M116.755934
Status	Udgivet - 11 nov. 2016

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Saederup, K. L., Stødkilde-Jørgensen, K., Graversen, J. H., Dickson, C. F., Etzerodt, A., Hansen, S. W. K., Fago, A., Gell, D., Andersen, C. B. F., & Moestrup, S. K. (2016). The Staphylococcus aureus Protein IsdH Inhibits Host Hemoglobin Scavenging to Promote Heme Acquisition by the Pathogen. Journal of Biological Chemistry, 291(46), 23989-23998. https://doi.org/10.1074/jbc.M116.755934

@article{29fc5c087bee4848b0f916ea92a3a00d,

title = "The Staphylococcus aureus Protein IsdH Inhibits Host Hemoglobin Scavenging to Promote Heme Acquisition by the Pathogen",

abstract = "Hemolysis is a complication in septic infections with Staphylococcus aureus, which utilizes the released Hb as an iron source. S. aureus can acquire heme in vitro from hemoglobin (Hb) by a heme-sequestering mechanism that involves proteins from the S. aureus iron-regulated surface determinant (Isd) system. However, the host has its own mechanism to recapture the free Hb via haptoglobin (Hp) binding and uptake of Hb-Hp by the CD163 receptor in macrophages. It has so far remained unclear how the Isd system competes with this host iron recycling system in situ to obtain the important nutrient. By binding and uptake studies, we now show that the IsdH protein, which serves as an Hb receptor in the Isd system, directly interferes with the CD163-mediated clearance by binding the Hb-Hp complex and inhibiting CD163 recognition. Analysis of truncated IsdH variants including one or more of three near iron transporter domains, IsdH(N1), IsdH(N2), and IsdH(N3), revealed that Hb binding of IsdH(N1) and IsdH(N2) accounted for the high affinity for Hb-Hp complexes. The third near iron transporter domain, IsdH(N3), exhibited redox-dependent heme extraction, when Hb in the Hb-Hp complex was in the oxidized met form but not in the reduced oxy form. IsdB, the other S. aureus Hb receptor, failed to extract heme from Hb-Hp, and it was a poor competitor for Hb-Hp binding to CD163. This indicates that Hb recognition by IsdH, but not by IsdB, sterically inhibits the receptor recognition of Hb-Hp. This function of IsdH may have an overall stimulatory effect on S. aureus heme acquisition and growth.",

keywords = "cell surface receptor, hemoglobin, iron, macrophage, Staphylococcus aureus (S, aureus), CD163, Iron-regulated Surface Determinant, IsdH, haptoglobin, heme acquisition, CYSTEINE-RICH DOMAIN, RECEPTOR CD163, TRANSPORTER DOMAINS, SURFACE PROTEIN, MOLECULAR-BASIS, HAPTOGLOBIN, IRON, BINDING, COMPLEX, SUSCEPTIBILITY",

author = "Saederup, {Kirstine Lindhardt} and Kristian St{\o}dkilde-J{\o}rgensen and Graversen, {Jonas Heilskov} and Dickson, {Claire F.} and Anders Etzerodt and Hansen, {Soren Werner Karlskov} and Angela Fago and David Gell and Andersen, {Christian Brix Folsted} and Moestrup, {Soren Kragh}",

year = "2016",

month = nov,

day = "11",

doi = "10.1074/jbc.M116.755934",

language = "English",

volume = "291",

pages = "23989--23998",

journal = "Journal of Biological Chemistry",

issn = "0021-9258",

publisher = "American Society for Biochemistry and Molecular Biology Inc.",

number = "46",

}

Saederup, KL, Stødkilde-Jørgensen, K, Graversen, JH, Dickson, CF, Etzerodt, A, Hansen, SWK, Fago, A, Gell, D, Andersen, CBF & Moestrup, SK 2016, 'The Staphylococcus aureus Protein IsdH Inhibits Host Hemoglobin Scavenging to Promote Heme Acquisition by the Pathogen', Journal of Biological Chemistry, bind 291, nr. 46, s. 23989-23998. https://doi.org/10.1074/jbc.M116.755934

The Staphylococcus aureus Protein IsdH Inhibits Host Hemoglobin Scavenging to Promote Heme Acquisition by the Pathogen. / Saederup, Kirstine Lindhardt; Stødkilde-Jørgensen, Kristian; Graversen, Jonas Heilskov et al.
I: Journal of Biological Chemistry, Bind 291, Nr. 46, 11.11.2016, s. 23989-23998.

Publikation: Bidrag til tidsskrift/Konferencebidrag i tidsskrift /Bidrag til avis › Tidsskriftartikel › Forskning › peer review

TY - JOUR

T1 - The Staphylococcus aureus Protein IsdH Inhibits Host Hemoglobin Scavenging to Promote Heme Acquisition by the Pathogen

AU - Saederup, Kirstine Lindhardt

AU - Stødkilde-Jørgensen, Kristian

AU - Graversen, Jonas Heilskov

AU - Dickson, Claire F.

AU - Etzerodt, Anders

AU - Hansen, Soren Werner Karlskov

AU - Fago, Angela

AU - Gell, David

AU - Andersen, Christian Brix Folsted

AU - Moestrup, Soren Kragh

PY - 2016/11/11

Y1 - 2016/11/11

N2 - Hemolysis is a complication in septic infections with Staphylococcus aureus, which utilizes the released Hb as an iron source. S. aureus can acquire heme in vitro from hemoglobin (Hb) by a heme-sequestering mechanism that involves proteins from the S. aureus iron-regulated surface determinant (Isd) system. However, the host has its own mechanism to recapture the free Hb via haptoglobin (Hp) binding and uptake of Hb-Hp by the CD163 receptor in macrophages. It has so far remained unclear how the Isd system competes with this host iron recycling system in situ to obtain the important nutrient. By binding and uptake studies, we now show that the IsdH protein, which serves as an Hb receptor in the Isd system, directly interferes with the CD163-mediated clearance by binding the Hb-Hp complex and inhibiting CD163 recognition. Analysis of truncated IsdH variants including one or more of three near iron transporter domains, IsdH(N1), IsdH(N2), and IsdH(N3), revealed that Hb binding of IsdH(N1) and IsdH(N2) accounted for the high affinity for Hb-Hp complexes. The third near iron transporter domain, IsdH(N3), exhibited redox-dependent heme extraction, when Hb in the Hb-Hp complex was in the oxidized met form but not in the reduced oxy form. IsdB, the other S. aureus Hb receptor, failed to extract heme from Hb-Hp, and it was a poor competitor for Hb-Hp binding to CD163. This indicates that Hb recognition by IsdH, but not by IsdB, sterically inhibits the receptor recognition of Hb-Hp. This function of IsdH may have an overall stimulatory effect on S. aureus heme acquisition and growth.

AB - Hemolysis is a complication in septic infections with Staphylococcus aureus, which utilizes the released Hb as an iron source. S. aureus can acquire heme in vitro from hemoglobin (Hb) by a heme-sequestering mechanism that involves proteins from the S. aureus iron-regulated surface determinant (Isd) system. However, the host has its own mechanism to recapture the free Hb via haptoglobin (Hp) binding and uptake of Hb-Hp by the CD163 receptor in macrophages. It has so far remained unclear how the Isd system competes with this host iron recycling system in situ to obtain the important nutrient. By binding and uptake studies, we now show that the IsdH protein, which serves as an Hb receptor in the Isd system, directly interferes with the CD163-mediated clearance by binding the Hb-Hp complex and inhibiting CD163 recognition. Analysis of truncated IsdH variants including one or more of three near iron transporter domains, IsdH(N1), IsdH(N2), and IsdH(N3), revealed that Hb binding of IsdH(N1) and IsdH(N2) accounted for the high affinity for Hb-Hp complexes. The third near iron transporter domain, IsdH(N3), exhibited redox-dependent heme extraction, when Hb in the Hb-Hp complex was in the oxidized met form but not in the reduced oxy form. IsdB, the other S. aureus Hb receptor, failed to extract heme from Hb-Hp, and it was a poor competitor for Hb-Hp binding to CD163. This indicates that Hb recognition by IsdH, but not by IsdB, sterically inhibits the receptor recognition of Hb-Hp. This function of IsdH may have an overall stimulatory effect on S. aureus heme acquisition and growth.

KW - cell surface receptor

KW - hemoglobin

KW - iron

KW - macrophage

KW - Staphylococcus aureus (S

KW - aureus)

KW - CD163

KW - Iron-regulated Surface Determinant

KW - IsdH

KW - haptoglobin

KW - heme acquisition

KW - CYSTEINE-RICH DOMAIN

KW - RECEPTOR CD163

KW - TRANSPORTER DOMAINS

KW - SURFACE PROTEIN

KW - MOLECULAR-BASIS

KW - HAPTOGLOBIN

KW - IRON

KW - BINDING

KW - COMPLEX

KW - SUSCEPTIBILITY

UR - http://www.scopus.com/inward/record.url?scp=84995578540&partnerID=8YFLogxK

U2 - 10.1074/jbc.M116.755934

DO - 10.1074/jbc.M116.755934

M3 - Journal article

C2 - 27681593

SN - 0021-9258

VL - 291

SP - 23989

EP - 23998

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

IS - 46

ER -

The Staphylococcus aureus Protein IsdH Inhibits Host Hemoglobin Scavenging to Promote Heme Acquisition by the Pathogen

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