Histidine-rich glycoprotein is a novel plasma pattern recognition molecule that recruits IgG to facilitate necrotic cell clearance via FcγRI on phagocytes

Poon, Ivan K. H.; Hulett, Mark D.; Parish, Christopher R.

doi:10.1182/blood-2009-07-234013

Cited by 41 publications

(68 citation statements)

References 51 publications

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“…The phospholipid code can be maintained or changed by enzymes that directly modify phospholipid head groups (phospholipid modifiers) or by phospholipid transporters that regulate the arrangement of lipids present on each side of the phospholipid bilayer. It is important to note that the intracellular phospholipid code can also be displayed on other organelles rich glycoprotein and mannose-binding lectin can detect other types of phospholipids such as PI(4)P and PA on necrotic cells to facilitate their removal by phagocytes 3,[21][22][23] (Figure 2b). …”

Section: Box 1 Phospholipids As Key Regulators Of Intracellular Procementioning

confidence: 99%

The phospholipid code: a key component of dying cell recognition, tumor progression and host–microbe interactions

2015

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A significant effort is made by the cell to maintain certain phospholipids at specific sites. It is well described that proteins involved in intracellular signaling can be targeted to the plasma membrane and organelles through phospholipid-binding domains. Thus, the accumulation of a specific combination of phospholipids, denoted here as the 'phospholipid code', is key in initiating cellular processes. Interestingly, a variety of extracellular proteins and pathogen-derived proteins can also recognize or modify phospholipids to facilitate the recognition of dying cells, tumorigenesis and host-microbe interactions. In this article, we discuss the importance of the phospholipid code in a range of physiological and pathological processes.

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Section: Box 1 Phospholipids As Key Regulators Of Intracellular Procementioning

confidence: 99%

The phospholipid code: a key component of dying cell recognition, tumor progression and host–microbe interactions

2015

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“…The N1 and N2 terminal domains of HRG are also implicated in the control of immune functioning through interactions with C1q, IgG, and FcgRI. 4,9 HRG regulates the formation of new blood vessels in both a pro-and antiangiogenic manner. The proangiogenic activity of HRG stems from its high affinity toward thrombospondin, an inhibitor of angiogenesis, via CD36/LIMP-2/EMP structural homology (CLESH) motifs contained within its C-terminal domain.…”

Section: Introductionmentioning

confidence: 99%

“…In plasma, HRG binds to and regulates the function of a diverse variety of targets that include fibrinogen, plasminogen, thrombospondin, immunoglobulin G (IgG), complement factors, and heparin as well as cell-surface molecules such as Fcg receptors and heparan sulfate. [1][2][3][4][5][6][7][8][9] HRG binds divalent metal cations within the HRR. 10 In particular, Zn 21 is known to bind this region and can modulate HRG activity by altering the protein's affinity for other targets.…”

Section: Introductionmentioning

confidence: 99%

Crystal structure of histidine-rich glycoprotein N2 domain reveals redox activity at an interdomain disulfide bridge: implications for angiogenic regulation

Kassaar¹,

McMahon

Thompson³

et al. 2014

Blood

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Key Points• The x-ray crystal structure of the N2 domain from HRG at 1.93Å resolution is presented.• The structure reveals an S-glutathionyl adduct at Cys185, which has implications for angiogenic regulation.Histidine-rich glycoprotein (HRG) is a plasma protein consisting of 6 distinct functional domains and is an important regulator of key cardiovascular processes, including angiogenesis and coagulation. The protein is composed of 2 N-terminal domains (N1 and N2), 2 proline-rich regions (PRR1 and PRR2) that flank a histidine-rich region (HRR), and a C-terminal domain. To date, structural information of HRG has largely come from sequence analysis and spectroscopic studies. It is thought that an HRG fragment containing the HRR, released via plasmin-mediated cleavage, acts as a negative regulator of angiogenesis in vivo. However, its release also requires cleavage of a disulphide bond suggesting that its activity is mediated by a redox process. Here, we present a 1.93Å resolution crystal structure of the N2 domain of serum-purified rabbit HRG. The structure confirms that the N2 domain, which along with the N1 domain, forms an important molecular interaction site on HRG, possesses a cystatin-like fold composed of a 5-stranded antiparallel b-sheet wrapped around a 5-turn a-helix. A native N-linked glycosylation site was identified at Asn184. Moreover, the structure reveals the presence of an S-glutathionyl adduct at Cys185, which has implications for the redox-mediated release of the antiangiogenic cleavage product from HRG. (Blood. 2014;123(12):1948-1955 Introduction Histidine-rich glycoprotein (HRG) is a plasma protein that regulates angiogenesis, coagulation, and immune function in vertebrates. Human HRG has an approximate mass of 70 kDa and is present in plasma at low micromolar concentrations (ca ;1.5 mM). The protein is arranged into 6 domains: 2 N-terminal domains (N1 and N2), a central histidine-rich region (HRR) flanked by 2 proline rich regions (PRR1 and PRR2), and a C-terminal domain (C). The N1, N2, and C domains are highly conserved between species, as is an arrangement of 6 disulfide bridges (Figure 1). In plasma, HRG binds to and regulates the function of a diverse variety of targets that include fibrinogen, plasminogen, thrombospondin, immunoglobulin G (IgG), complement factors, and heparin as well as cell-surface molecules such as Fcg receptors and heparan sulfate.1-9 HRG binds divalent metal cations within the HRR. 10 In particular, Zn 21 is known to bind this region and can modulate HRG activity by altering the protein's affinity for other targets. 11HRG is heavily glycosylated; the human protein has 6 putative N-linked glycosylation sites.11 The histidine-and proline-rich regions are predicted to be intrinsically disordered but N1, N2, and the C-terminal domains are likely to have ordered structures. The N1 and N2 domains share a high degree of sequence similarity to members of the cystatin superfamily of cysteine protease inhibitors.12 Type 1 cystatins (also known as stefins) are characterized b...

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“…Mantovani and Sica [29] revealed the antitumor activity of HRG as it is not only increased tumor infiltration by antigen-presenting DCs, cytolytic NK cells, and cytotoxic T-lymphocytes but also enhances their antigen presentation and tumor cell lysis potential, immune changes known to inhibit tumor growth. The possible, increasing levels of HRG in malignant cases might be due to the recognition of ''malignant danger'', in line with its presumed role as a ''pattern recognition molecule'' [16]. We could not find any literature evaluating serum HRG protein or its expression levels in ALL.…”

Section: Discussionmentioning

confidence: 61%

“…Histidine-rich glycoprotein (HRG) is a multifunctional plasma protein with two cystatin-like domains and a wide spectrum of targets and functions [16]. Extensive research studied the potential role of HRG in carcinogenesis, however, its effect on overall survival remains to be clearly determined.…”

Section: Discussionmentioning

confidence: 99%

Diagnostic and Prognostic Significance of Histidine-Rich Glycoprotein in Acute Lymphoblastic Leukemia

Ahmed¹,

Almogbel²,

Khirry³

et al. 2017

OJBD

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Background: Histidine-rich glycoprotein (HRG), a multifunctional plasma protein, has a regulatory role in homeostasis, angiogenesis, and immunity; which in turn could greatly affect tumor control and metastasis. Objectives: To assess the possible role of HRG in acute lymphoblastic leukemia (ALL) tumorgenesis and follow-up. Design and Methods: HRG was quantitatively measured in serum by ELISA and its expression was assessed by real-time PCR (qPCR) in 35 patients with ALL and compared to same 25 ALL patients after induction therapy and 30 age and sex matched healthy control subjects. Results: HRG-serum protein (at cutoff value 63.55 pg/ml) and HRG-RNA (at cutoff value 0.955) were positive in all ALL patients before therapy, but in only 76% after therapy for HRG-protein and 60% for HRG-RNA and they could not be detected in the control group; P < 0.001. Additionally, the serum HRG level showed a significant positive correlation with its expression level, bone marrow blast percentage, peripheral blood blast count, P < 0.01. Also its serum and expression levels were positively related to the poor risk Philadelphia chromosome; P < 0.01. Conclusions: HRG (protein and RNA) might be considered as a novel diagnostic and prognostic marker in ALL. HRG-serum protein level, detected by simple methodology of ELISA, has more significant advantages than its expression level, motivating its application in large clinical studies as a potential marker.

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Histidine-rich glycoprotein is a novel plasma pattern recognition molecule that recruits IgG to facilitate necrotic cell clearance via FcγRI on phagocytes

Cited by 41 publications

References 51 publications

The phospholipid code: a key component of dying cell recognition, tumor progression and host–microbe interactions

The phospholipid code: a key component of dying cell recognition, tumor progression and host–microbe interactions

Crystal structure of histidine-rich glycoprotein N2 domain reveals redox activity at an interdomain disulfide bridge: implications for angiogenic regulation

Diagnostic and Prognostic Significance of Histidine-Rich Glycoprotein in Acute Lymphoblastic Leukemia

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