Functional Regulation of the Plasma Protein Histidine-Rich Glycoprotein by Zn2+ in Settings of Tissue Injury

Priebatsch, Kristin; Kvansakul, Marc; Poon, Ivan K. H.; Hulett, Mark D.

doi:10.3390/biom7010022

Cited by 28 publications

(26 citation statements)

References 112 publications

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“…In accord with earlier reports, we observed severe dysregulation of proteins associated with platelet activation and degranulation ( Figure 4b , Category #2 ) ( Manne et al, 2020b ). For example, abundance of histidine-rich glycoprotein (HRG) - which binds heme, heparin, thrombospondin, and plasminogen ( Priebatsch et al, 2017 ) - was significantly reduced in patients with COVID-19, with the mean level 1.8-fold lower than in non-COVID-19 patients ( Supplementary Figure 4 , p-value = 8.138 × 10 −12 ). Similarly, abundances of GPLD1 and CLEC3B significantly decreased in COVID-19 and correlated with disease severity ( Figure 4b Category #2 , Supplementary Figure 4 ).…”

Section: Resultsmentioning

confidence: 99%

Large-scale Multi-omic Analysis of COVID-19 Severity

Overmyer

Miller

Balnis

et al. 2020

Preprint

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We performed RNA-Seq and high-resolution mass spectrometry on 128 blood samples from COVID-19 positive and negative patients with diverse disease severities. Over 17,000 transcripts, proteins, metabolites, and lipids were quantified and associated with clinical outcomes in a curated relational database, uniquely enabling systems analysis and cross-ome correlations to molecules and patient prognoses. We mapped 219 molecular features with high significance to COVID-19 status and severity, many involved in complement activation, dysregulated lipid transport, and neutrophil activation. We identified sets of covarying molecules, e.g., protein gelsolin and metabolite citrate or plasmalogens and apolipoproteins, offering pathophysiological insights and therapeutic suggestions. The observed dysregulation of platelet function, blood coagulation, acute phase response, and endotheliopathy further illuminated the unique COVID-19 phenotype. We present a web-based tool (covid-omics.app) enabling interactive exploration of our compendium and illustrate its utility through a comparative analysis with published data and a machine learning approach for prediction of COVID-19 severity.

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Section: Resultsmentioning

confidence: 99%

Large-scale Multi-omic Analysis of COVID-19 Severity

Overmyer

Miller

Balnis

et al. 2020

Preprint

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“…Interestingly, not only low pH but also Zn 2ϩ is able to impose a positive charge on the histidine-rich domain of HRG (1,8). In fact, the ability of HRG to interact with cell surface HS at neutral pH markedly increases following the interaction of HRG with Zn 2ϩ at physiological concentrations of Zn 2ϩ (ϳ10 to 20 M) (9).…”

Section: Discussionmentioning

confidence: 99%

Histidine-Rich Glycoprotein Inhibits HIV-1 Infection in a pH-Dependent Manner

Dantas

Díaz

Gerber

et al. 2019

J Virol

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Histidine-rich glycoprotein (HRG) is an abundant plasma protein with a multidomain structure, allowing its interaction with many ligands, including phospholipids, plasminogen, fibrinogen, IgG antibodies, and heparan sulfate. HRG has been shown to regulate different biological responses, such as angiogenesis, coagulation, and fibrinolysis. Here, we found that HRG almost completely abrogated the infection of Ghost cells, Jurkat cells, CD4+ T cells, and macrophages by HIV-1 at a low pH (range, 6.5 to 5.5) but not at a neutral pH. HRG was shown to interact with the heparan sulfate expressed by target cells, inhibiting an early postbinding step associated with HIV-1 infection. More importantly, by acting on the viral particle itself, HRG induced a deleterious effect, which reduces viral infectivity. Because cervicovaginal secretions in healthy women show low pH values, even after semen deposition, our observations suggest that HRG might represent a constitutive defense mechanism in the vaginal mucosa. Of note, low pH also enabled HRG to inhibit the infection of HEp-2 cells and Vero cells by respiratory syncytial virus (RSV) and herpes simplex virus 2 (HSV-2), respectively, suggesting that HRG might display broad antiviral activity under acidic conditions. IMPORTANCE Vaginal intercourse represents a high-risk route for HIV-1 transmission. The efficiency of male-to-female HIV-1 transmission has been estimated to be 1 in every 1,000 episodes of sexual intercourse, reflecting the high degree of protection conferred by the genital mucosa. However, the contribution of different host factors to the protection against HIV-1 at mucosal surfaces remains poorly defined. Here, we report for the first time that acidic values of pH enable the plasma protein histidine-rich glycoprotein (HRG) to strongly inhibit HIV-1 infection. Because cervicovaginal secretions usually show low pH values, our observations suggest that HRG might represent a constitutive antiviral mechanism in the vaginal mucosa. Interestingly, infection by other viruses, such as respiratory syncytial virus and herpes simplex virus 2, was also markedly inhibited by HRG at low pH values, suggesting that extracellular acidosis enables HRG to display broad antiviral activity.

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“… 58 When the net charge of HRG becomes positive, either through a change in protonation of the histidine residues (through a change in pH) or through binding of those residues to metal cations, the conformation of the molecule changes, influencing its affinity for binding its ligands. 19 , 48 , 58 – 62 …”

Section: Impact Of Zn 2+ On Protein–gag Interactiomentioning

confidence: 99%