Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Heparanase, cell signaling, and viral infections.

ABSTRACT: Heparanase (HPSE) is a multifunctional protein endowed with many non-enzymatic functions and a unique enzymatic activity as an endo-?-D-glucuronidase. The latter allows it to serve as a key modulator of extracellular matrix (ECM) via a well-regulated cleavage of heparan sulfate side chains of proteoglycans at cell surfaces. The cleavage and associated changes at the ECM cause release of multiple signaling molecules with important cellular and pathological functions. New and emerging data suggest that both enzymatic as well as non-enzymatic functions of HPSE are important for health and illnesses including viral infections and virally induced cancers. This review summarizes recent findings on the roles of HPSE in activation, inhibition, or bioavailability of key signaling molecules such as AKT, VEGF, MAPK-ERK, and EGFR, which are known regulators of common viral infections in immune and non-immune cell types. Altogether, our review provides a unique overview of HPSE in cell-survival signaling pathways and how they relate to viral infections.

SUBMITTER: Koganti R

PROVIDER: S-EPMC7252873 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

Heparanase, cell signaling, and viral infections.

Koganti Raghuram R Suryawanshi Rahul R Shukla Deepak D

Cellular and molecular life sciences : CMLS 20200527 24

Heparanase (HPSE) is a multifunctional protein endowed with many non-enzymatic functions and a unique enzymatic activity as an endo-β-D-glucuronidase. The latter allows it to serve as a key modulator of extracellular matrix (ECM) via a well-regulated cleavage of heparan sulfate side chains of proteoglycans at cell surfaces. The cleavage and associated changes at the ECM cause release of multiple signaling molecules with important cellular and pathological functions. New and emerging data suggest ...[more]

PMID: 32462405

Similar Datasets

Structural Insights into Pixatimod (PG545) Inhibition of Heparanase, a Key Enzyme in Cancer and Viral Infections.

Project description:Pixatimod (PG545), a heparan sulfate (HS) mimetic and anticancer agent currently in clinical trials, is a potent inhibitor of heparanase. Heparanase is an endo-β-glucuronidase that degrades HS in the extracellular matrix and basement membranes and is implicated in numerous pathological processes such as cancer and viral infections, including SARS-CoV-2. To understand how PG545 interacts with heparanase, we firstly carried out a conformational analysis through a combination of NMR experiments and molecular modelling which showed that the reducing end β-D-glucose residue of PG545 adopts a distorted conformation. This was followed by docking and molecular dynamics simulations to study the interactions of PG545 with heparanase, revealing that PG545 is able to block the active site by binding in different conformations, with the cholestanol side-chain making important hydrophobic interactions. While PG545 blocks its natural substrate HS from binding to the active site, small synthetic heparanase substrates are only partially excluded, and thus pentasaccharide or larger substrates are preferred for assaying this class of inhibitor. This study provides new insights for the design of next-generation heparanase inhibitors and substrates.

| S-EPMC9303737 | biostudies-literature

Microbiota regulation of viral infections through interferon signaling.

Project description:The interferon (IFN) response is the major early innate immune response against invading viral pathogens and is even capable of mediating sterilizing antiviral immunity without the support of the adaptive immune system. Cumulative evidence suggests that the gut microbiota can modulate IFN responses, indirectly determining virological outcomes. This review outlines our current knowledge of the interactions between the gut microbiota and IFN responses and dissects the different mechanisms by which the gut microbiota may alter IFN expression to diverse viral infections. This knowledge offers a basis for translating experimental evidence from animal studies into the human context and identifies avenues for leveraging the gut microbiota-IFN-virus axis to improve control of viral infections and performance of viral vaccines.

| S-EPMC9344482 | biostudies-literature

Dysregulation of host cell calcium signaling during viral infections: Emerging paradigm with high clinical relevance.

Project description:Viral infections are one of the leading causes of human illness. Viruses take over host cell signaling cascades for their replication and infection. Calcium (Ca2+) is a versatile and ubiquitous second messenger that modulates plethora of cellular functions. In last two decades, a critical role of host cell Ca2+ signaling in modulating viral infections has emerged. Furthermore, recent literature clearly implicates a vital role for the organellar Ca2+ dynamics (influx and efflux across organelles) in regulating virus entry, replication and severity of the infection. Therefore, it is not surprising that a number of viral infections including current SARS-CoV-2 driven COVID-19 pandemic are associated with dysregulated Ca2+ homeostasis. The focus of this review is to first discuss the role of host cell Ca2+ signaling in viral entry, replication and egress. We further deliberate on emerging literature demonstrating hijacking of the host cell Ca2+ dynamics by viruses. In particular, a variety of viruses including SARS-CoV-2 modulate lysosomal and cytosolic Ca2+ signaling for host cell entry and replication. Moreover, we delve into the recent studies, which have demonstrated the potential of several FDA-approved drugs targeting Ca2+ handling machinery in inhibiting viral infections. Importantly, we discuss the prospective of targeting intracellular Ca2+ signaling for better management and treatment of viral pathogenesis including COVID-19. Finally, we highlight the key outstanding questions in the field that demand critical and timely attention.

| S-EPMC8299155 | biostudies-literature

Notch4 signaling limits regulatory T-cell-mediated tissue repair and promotes severe lung inflammation in viral infections.

Project description:A cardinal feature of COVID-19 is lung inflammation and respiratory failure. In a prospective multi-country cohort of COVID-19 patients, we found that increased Notch4 expression on circulating regulatory T (Treg) cells was associated with disease severity, predicted mortality, and declined upon recovery. Deletion of Notch4 in Treg cells or therapy with anti-Notch4 antibodies in conventional and humanized mice normalized the dysregulated innate immunity and rescued disease morbidity and mortality induced by a synthetic analog of viral RNA or by influenza H1N1 virus. Mechanistically, Notch4 suppressed the induction by interleukin-18 of amphiregulin, a cytokine necessary for tissue repair. Protection by Notch4 inhibition was recapitulated by therapy with Amphiregulin and, reciprocally, abrogated by its antagonism. Amphiregulin declined in COVID-19 subjects as a function of disease severity and Notch4 expression. Thus, Notch4 expression on Treg cells dynamically restrains amphiregulin-dependent tissue repair to promote severe lung inflammation, with therapeutic implications for COVID-19 and related infections.

| S-EPMC8080416 | biostudies-literature

Electrically regulated cell-based intervention for viral infections.

Project description:This work reports on an engineered cell that-when electrically stimulated-synthesizes a desired protein, that is, ES-Biofactory. The platform has been used to express interferon (IFN)-β as a universal antiviral protein. Compelling evidence indicates the inevitability of new pandemics and drives the need for a pan-viral intervention that may be quickly deployed while more specific vaccines are in development. Toward this goal, a fast-growing mammalian cell (Chassis) has been engineered with multiple synthetic elements. These include-(1) a voltage-gated Ca2+ channel (Voltage-Sensor) that, upon sensing the electric field, activates the (2) Ca2+-mediated signaling pathway (Actuator) to upregulate (3) IFN-β, via an engineered antiviral transgene (Effector), that is, ES-Biofactory➔IFN-β. The antiviral effects of the ES-Biofactory➔IFN-β have been validated on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected cells. The irradiated ES-Biofactory, that does not exhibit oncogenic capacity, continues to exert antiviral effect. The resulting ES-Biofactory➔IFN-β uses a novel signaling pathway that, unlike the natural IFN synthesis pathway, is not subject to viral interference. Once clinically validated, the ES-Biofactory will be a universal antiviral cell therapy that can be immediately deployed in the event of an outbreak. The platform may also be useful in treating other diseases including cancer and autoimmune disorders.

| S-EPMC10013824 | biostudies-literature

Viral Activation of Heparanase Drives Pathogenesis of Herpes Simplex Virus-1.

Project description:Herpes simplex virus-1 (HSV-1) causes lifelong recurrent pathologies without a cure. How infection by HSV-1 triggers disease processes, especially in the immune-privileged avascular human cornea, remains a major unresolved puzzle. It has been speculated that a cornea-resident molecule must tip the balance in favor of pro-inflammatory and pro-angiogenic conditions observed with herpetic, as well as non-herpetic, ailments of the cornea. Here, we demonstrate that heparanase (HPSE), a host enzyme, is the molecular trigger for multiple pathologies associated with HSV-1 infection. In human corneal epithelial cells, HSV-1 infection upregulates HPSE in a manner dependent on HSV-1 infected cell protein 34.5. HPSE then relocates to the nucleus to regulate cytokine production, inhibits wound closure, enhances viral spread, and thus generates a toxic local environment. Overall, our findings implicate activated HPSE as a driver of viral pathogenesis and call for further attention to this host protein in infection and other inflammatory disorders.

| S-EPMC5557421 | biostudies-literature

Signaling sphingolipids are biomarkers for atopic dermatitis prone to disseminated viral infections.

Project description:BackgroundLife-threatening viral diseases such as eczema herpeticum (EH) and eczema vaccinatum (EV) occur in <5% of individuals with atopic dermatitis (AD). The diagnosis of AD, however, excludes all individuals with AD from smallpox vaccination.ObjectivesWe sought to identify circulatory and skin lipid biomarkers associated with EH and EV.MethodsStratum corneum and plasma samples from 15 subjects with AD and a history of EH, 13 age- and gender-matched subjects with AD and without EH history, and 13 healthy nonatopic (NA) controls were analyzed by liquid chromatography tandem mass spectrometry for sphingolipid content. Sphingosine-1-phosphate (S1P) and ceramide levels were validated in plasma samples from the Atopic Dermatitis Vaccinia Network/Atopic Dermatitis Research Network repository (12 NA, 12 AD, 23 EH) and plasma from 7 subjects with EV and 7 matched subjects with AD. S1P lyase was downregulated in human primary keratinocytes to evaluate its effect on herpes simplex virus 1 (HSV-1) replication in vitro.ResultsThe stratum corneum of patients with EH demonstrated significantly higher levels of free sphingoid bases than those in patients who were NA, indicating enhanced sphingolipid turnover in keratinocytes (P < .05). Plasma from 2 independent cohorts of patients with EH had a significantly increased S1P/ceramide ratio in subjects with EH versus those with AD and or who were NA (P < .01). The S1P level in plasma from subjects with EV was twice the level in plasma from subjects with AD (mean = 1,533 vs 732 pmol/mL; P < .001). Downregulation of S1P lyase expression with silencing RNA led to an increased S1P level and doubled HSV-1 titer in keratinocytes.ConclusionsOur data point to long-term abnormalities in the S1P signaling system as a biomarker for previous disseminated viral diseases and a potential treatment target in recurring infections.

| S-EPMC9463085 | biostudies-literature

Respiratory viral infections

Project description:Molecular analysis of respiratory viruses and the host response to both infection and vaccination have transformed our understanding of these ubiquitous pathogens. Polymerase chain reaction for the rapid and accurate diagnosis of viral infections has led to a better understanding of the epidemiology and impact of many common respiratory viruses and resulted in better patient care. Over the past decade a number of new respiratory viruses including human metapneumovirus and new coronaviruses have been discovered using molecular techniques such as random primer amplification, pan-viral array and next generation sequencing. Analysis of the host transcriptional response during respiratory viral infection using in-vitro, animal models and natural and experimental human challenge have furthered the understanding of the mechanisms and predictors of severe disease and may identify potential therapeutic targets to prevent and ameliorate illness.

| S-EPMC7149961 | biostudies-literature

Heparanase Modulates Shh and Wnt3a Signaling in Human Medulloblastoma Cells.

Project description:The pathogenesis of medulloblastoma (MB), the most common and aggressive brain tumor in children, is poorly understood. MB tumors respond to factors secreted by cerebellar Purkinje neurons such as Sonic hedgehog (Shh) and Wnt3a. Understanding the modulation of Shh/Wnt signaling is critical to developing new MB treatments. Shh and Wnt3a induce MB cell proliferation, and bind heparan sulfate glycosaminoglycan chains (HS-GAG). HS-GAG are components of syndecans: cell surface HS proteoglycans (HSPG) which act as co-receptors for extracellular matrix based ligands, and are targets of heparanase (HPSE). We hypothesized that extracellular HPSE activity can modulate MB intracellular signaling of Shh/Wnt3a, involving syndecans 1/4 carboxy terminal-associated proteins and downstream targets. We compared the regulation of Shh/Wnt3a signaling subsequent to treatment with exogenous human active HPSE in MB lines possessing increased invasive abilities. We identified GEF-H1, a small GTPase guanine nucleotide exchange factor, as a new component of a syndecan signaling complex. Secondly, we demonstrated that HPSE modulated Shh/Wnt3 dependent expression and intracellular distribution of GEF-H1, β-catenin, and N-Myc. Thirdly, HPSE modulated Shh/Wnt3a - dependent gene expression of HSPG and Gli transcription factors. Fourthly, pretreatment with HPSE, alone or prior to Shh/Wnt3a exposure, altered small GTPase (Rac1/RhoA) activities differentially, and promoted RhoA activation. Finally, the differential regulation of Rac1/RhoA activities by HPSE affected MB cell proliferation and invasion. Our results indicate that the HPSE/HSPG axis is implicated in critical MB cell signaling pathways with potential relevance for MB treatment.

| S-EPMC3063606 | biostudies-literature

CD4 T-cell immunotherapy for chronic viral infections and cancer.

Project description:During chronic infections and cancer, T cells progressively lose function and become exhausted. However, effective T-cell responses are necessary to ultimately control viral infections and tumors. Hence, strategies that either restore endogenous immune responses or provide functional T cells by adoptive immunotherapy need to be explored. CD8 T cells play a prominent role in viral infections, as well as cancer, but CD4 T cells are necessary to support CD8 T-cell function. In addition, CD4 T cells exert direct effector functions, induce optimal B-cell responses and orchestrate innate immunity. Therefore, we propose that adoptive transfer strategies should exploit CD4 T cells alone or in combination with CD8 T cells, for the treatment of chronic infections and cancer. Furthermore, since adoptively transferred cells are subject to exhaustion, combining adoptive transfer therapy with immunotherapies that inhibit T-cell exhaustion should maximize the longevity and success rate of responses.

| S-EPMC3864579 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data