The Binding of the Circumsporozoite Protein to Cell Surface Heparan Sulfate Proteoglycans Is Required forPlasmodiumSporozoite Attachment to Target Cells

During feeding by infected mosquitoes, malaria sporozoites are injected into the host's bloodstream and enter hepatocytes within minutes. The remarkable target cell specificity of this parasite may be explained by the presence of receptors for the region II-plus of the circumsporozoite protein (CS) on the basolateral domain of the plasma membrane of hepatocytes. We have now identified these receptors as heparan sulfate proteoglycans (HSPG). The binding of CS to the receptors is abolished by heparitinase treatment, indicating that the recognition of region II-plus is via the glycosaminoglycan chains. We have purified and partially characterized the CS-binding HSPGs from HepG2 cells. They have a molecular weight of 400,000-700,000, are tightly associated with the plasma membrane, and are released from the cell surface by very mild trypsinization, a property which the CS receptors share with the syndecan family of proteoglycans.

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Extracellular distribution of diffusible growth factors controlled by heparan sulfate proteoglycans during mammalian embryogenesis

Philosophical Transactions of the Royal Society B Biological Sciences ◽

10.1098/rstb.2013.0545 ◽

2014 ◽

Vol 369 (1657) ◽

pp. 20130545 ◽

Cited By ~ 40

Author(s):

Isao Matsuo ◽

Chiharu Kimura-Yoshida

Keyword(s):

Growth Factors ◽

Cell Surface ◽

Heparan Sulfate ◽

Cell Fate ◽

Heparan Sulfate Proteoglycans ◽

Target Cells ◽

Dependent Manner ◽

Mammalian Development ◽

Morphogenetic Protein ◽

And Control

During mouse embryogenesis, diffusible growth factors, i.e. fibroblast growth factors, Wnt, bone morphogenetic protein and Hedgehog family members, emanating from localized areas can travel through the extracellular space and reach their target cells to specify the cell fate and form tissue architectures in coordination. However, the mechanisms by which these growth factors travel great distances to their target cells and control the signalling activity as morphogens remain an enigma. Recent studies in mice and other model animals have revealed that heparan sulfate proteoglycans (HSPGs) located on the cell surface (e.g. syndecans and glypicans) and in the extracellular matrix (ECM; e.g. perlecan and agrin) play crucial roles in the extracellular distribution of growth factors. Principally, the function of HSPGs depends primarily on the fine features and localization of their heparan sulfate glycosaminoglycan chains. Cell-surface-tethered HSPGs retain growth factors as co-receptors and/or endocytosis mediators, and enzymatic release of HSPGs from the cell membrane allows HSPGs to transport or move multiple growth factors. By contrast, ECM-associated HSPGs function as a reservoir or barrier in a context-dependent manner. This review is focused on our current understanding of the extracellular distribution of multiple growth factors controlled by HSPGs in mammalian development.

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Heparan Sulfate Proteoglycans Are Required for Cellular Binding of the Hepatitis E Virus ORF2 Capsid Protein and for Viral Infection

Journal of Virology ◽

10.1128/jvi.00717-09 ◽

2009 ◽

Vol 83 (24) ◽

pp. 12714-12724 ◽

Cited By ~ 119

Author(s):

Manjula Kalia ◽

Vivek Chandra ◽

Sheikh Abdul Rahman ◽

Deepak Sehgal ◽

Shahid Jameel

Keyword(s):

Cell Surface ◽

Heparan Sulfate ◽

Capsid Protein ◽

Marked Reduction ◽

Electrostatic Interactions ◽

Hepatitis E Virus ◽

Hepatitis E ◽

Heparan Sulfate Proteoglycans ◽

Productive Infection ◽

Target Cells

ABSTRACT The hepatitis E virus (HEV), a nonenveloped RNA virus, is the causative agent of hepatitis E. The mode by which HEV attaches to and enters into target cells for productive infection remains unidentified. Open reading frame 2 (ORF2) of HEV encodes its major capsid protein, pORF2, which is likely to have the determinants for virus attachment and entry. Using an ∼56-kDa recombinant pORF2 that can self-assemble as virus-like particles, we demonstrated that cell surface heparan sulfate proteoglycans (HSPGs), specifically syndecans, play a crucial role in the binding of pORF2 to Huh-7 liver cells. Removal of cell surface heparan sulfate by enzymatic (heparinase) or chemical (sodium chlorate) treatment of cells or competition with heparin, heparan sulfate, and their oversulfated derivatives caused a marked reduction in pORF2 binding to the cells. Syndecan-1 is the most abundant proteoglycan present on these cells and, hence, plays a key role in pORF2 binding. Specificity is likely to be dictated by well-defined sulfation patterns on syndecans. We show that pORF2 binds syndecans predominantly via 6-O sulfation, indicating that binding is not entirely due to random electrostatic interactions. Using an in vitro infection system, we also showed a marked reduction in HEV infection of heparinase-treated cells. Our results indicate that, analogous to some enveloped viruses, a nonenveloped virus like HEV may have also evolved to use HSPGs as cellular attachment receptors.

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Mediation of human immunodeficiency virus type 1 binding by interaction of cell surface heparan sulfate proteoglycans with the V3 region of envelope gp120-gp41.

Journal of Virology ◽

10.1128/jvi.69.4.2233-2239.1995 ◽

1995 ◽

Vol 69 (4) ◽

pp. 2233-2239 ◽

Cited By ~ 158

Author(s):

G Roderiquez ◽

T Oravecz ◽

M Yanagishita ◽

D C Bou-Habib ◽

H Mostowski ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Cell Surface ◽

Heparan Sulfate ◽

Human Immunodeficiency Virus Type ◽

Virus Type ◽

Heparan Sulfate Proteoglycans ◽

Immunodeficiency Virus ◽

V3 Region ◽

Envelope Gp120

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Distinct glycosaminoglycan chain length and sulfation patterns required for cellular uptake of Tau, Aβ, and α-Synuclein

10.1101/207035 ◽

2017 ◽

Cited By ~ 1

Author(s):

Barbara E. Stopschinski ◽

Brandon B. Holmes ◽

Gregory M. Miller ◽

Jaime Vaquer-Alicea ◽

Linda C. Hsieh-Wilson ◽

...

Keyword(s):

Cell Surface ◽

Neurodegenerative Diseases ◽

Heparan Sulfate ◽

Chain Length ◽

Cellular Uptake ◽

Genetic Manipulation ◽

Heparan Sulfate Proteoglycans ◽

Cell Uptake ◽

Major Genes

AbstractTranscellular propagation of aggregate “seeds” has been proposed to mediate progression of neurodegenerative diseases in tauopathies and α-synucleinopathies. We have previously determined that tau and α-synuclein aggregates bind heparan sulfate proteoglycans (HSPGs) on the cell surface. This mediates uptake and intracellular seeding. The specificity and mode of binding to HSPGs has been unknown. We used modified heparins to determine the size and sulfation requirements of glycosaminoglycan (GAGs) binding to aggregates in biochemical and cell uptake and seeding assays. Aggregates of tau require a precise GAG architecture with defined sulfate moieties in the N- and 6-O-positions, whereas α-synuclein and Aβ rely slightly more on overall charge on the GAGs. To determine the genetic requirements for aggregate uptake, we individually knocked out the major genes of the HSPG synthesis pathway using CRISPR/Cas9 in HEK293T cells. Knockout of EXT1, EXT2 and EXTL3, N-sulfotransferase (NDST1), and 6-O-sulfotransferase (HS6ST2) significantly reduced tau uptake. α-Synuclein was not sensitive to HS6ST2 knockout. Good correlation between pharmacologic and genetic manipulation of GAG binding by tau and α-synuclein indicates specificity that may help elucidate a path to mechanism-based inhibition of transcellular propagation of pathology.

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Cooperation of Syndecan-2 and Syndecan-4 among Cell Surface Heparan Sulfate Proteoglycans in the Actin Cytoskeletal Organization of Lewis Lung Carcinoma Cells

The Journal of Biochemistry ◽

10.1093/jb/mvh015 ◽

2004 ◽

Vol 135 (1) ◽

pp. 129-137 ◽

Cited By ~ 27

Author(s):

Y. Kusano

Keyword(s):

Cell Surface ◽

Heparan Sulfate ◽

Lung Carcinoma ◽

Lewis Lung Carcinoma ◽

Heparan Sulfate Proteoglycans ◽

Carcinoma Cells ◽

Lewis Lung ◽

Cytoskeletal Organization ◽

Lung Carcinoma Cells ◽

Lewis Lung Carcinoma Cells

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Heparan Sulfate Proteoglycans May Promote or Inhibit Cancer Progression by Interacting with Integrins and Affecting Cell Migration

BioMed Research International ◽

10.1155/2015/453801 ◽

2015 ◽

Vol 2015 ◽

pp. 1-8 ◽

Cited By ~ 24

Author(s):

Mariana A. Soares ◽

Felipe C. O. B. Teixeira ◽

Miguel Fontes ◽

Ana Lúcia Arêas ◽

Marcelo G. Leal ◽

...

Keyword(s):

Cell Adhesion ◽

Cell Surface ◽

Heparan Sulfate ◽

Cancer Progression ◽

Heparan Sulfate Proteoglycans ◽

Transmembrane Receptors ◽

Surface Molecules ◽

Cell Matrix ◽

Cell Organization ◽

The Relationship

The metastatic disease is one of the main consequences of tumor progression, being responsible for most cancer-related deaths worldwide. This review intends to present and discuss data on the relationship between integrins and heparan sulfate proteoglycans in health and cancer progression. Integrins are a family of cell surface transmembrane receptors, responsible for cell-matrix and cell-cell adhesion. Integrins’ main functions include cell adhesion, migration, and survival. Heparan sulfate proteoglycans (HSPGs) are cell surface molecules that play important roles as cell receptors, cofactors, and overall direct or indirect contributors to cell organization. Both molecules can act in conjunction to modulate cell behavior and affect malignancy. In this review, we will discuss the different contexts in which various integrins, such asα5,αV,β1, andβ3, interact with HSPGs species, such as syndecans and perlecans, affecting tissue homeostasis.

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BETA2/NeuroD Protein Transduction Requires Cell Surface Heparan Sulfate Proteoglycans

Human Gene Therapy ◽

10.1089/hum.2007.18.ft-268 ◽

2006 ◽

Vol 0 (0) ◽

pp. 061206073830001

Author(s):

Hirofumi Noguchi ◽

Michiko Ueda ◽

Shinichi Matsumoto ◽

Naoya Kobayashi ◽

Shuji Hayashi

Keyword(s):

Cell Surface ◽

Heparan Sulfate ◽

Heparan Sulfate Proteoglycans ◽

Protein Transduction

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Interaction of an Outer Membrane Protein of Enterotoxigenic Escherichia coli with Cell Surface Heparan Sulfate Proteoglycans

Infection and Immunity ◽

10.1128/iai.70.3.1530-1537.2002 ◽

2002 ◽

Vol 70 (3) ◽

pp. 1530-1537 ◽

Cited By ~ 44

Author(s):

James M. Fleckenstein ◽

James T. Holland ◽

David L. Hasty

Keyword(s):

Escherichia Coli ◽

Epithelial Cell ◽

Epithelial Cells ◽

Cell Surface ◽

Heparan Sulfate ◽

Heparan Sulfate Proteoglycans ◽

Eukaryotic Cells ◽

Heparin Binding ◽

Wild Type ◽

E Coli

ABSTRACT We have previously shown that enterotoxigenic invasion protein A (Tia), a 25-kDa outer membrane protein encoded on an apparent pathogenicity island of enterotoxigenic Escherichia coli (ETEC) strain H10407, mediates attachment to and invasion into cultured human gastrointestinal epithelial cells. The epithelial cell receptor(s) for Tia has not been identified. Here we show that Tia interacts with cell surface heparan sulfate proteoglycans. Recombinant E. coli expressing Tia mediated invasion into wild-type epithelial cell lines but not invasion into proteoglycan-deficient cells. Furthermore, wild-type eukaryotic cells, but not proteoglycan-deficient eukaryotic cells, attached to immobilized polyhistidine-tagged recombinant Tia (rTia). Binding of epithelial cells to immobilized rTia was inhibited by exogenous heparan sulfate glycosaminoglycans but not by hyaluronic acid, dermatan sulfate, or chondroitin sulfate. Similarly, pretreatment of eukaryotic cells with heparinase I, but not pretreatment of eukaryotic cells with chrondroitinase ABC, inhibited attachment to rTia. In addition, we also observed heparin binding to both immobilized rTia and recombinant E. coli expressing Tia. Heparin binding was inhibited by a synthetic peptide representing a surface loop of Tia, as well as by antibodies directed against this peptide. Additional studies indicated that Tia, as a prokaryotic heparin binding protein, may also interact via sulfated proteoglycan molecular bridges with a number of mammalian heparan sulfate binding proteins. These findings suggest that the binding of Tia to host epithelial cells is mediated at least in part through heparan sulfate proteoglycans and that ETEC belongs on the growing list of pathogens that utilize these ubiquitous cell surface molecules as receptors.

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