Dataset Information

Retinal Proteoglycans Act as Cellular Receptors for Basement Membrane Assembly to Control Astrocyte Migration and Angiogenesis.

ABSTRACT: The basement membrane is crucial for cell polarity, adhesion, and motility, but how it is assembled on the cell surface remains unclear. Here, we find that ablation of glycosaminoglycan (GAG) side chains of proteoglycans in the neuroretina disrupts the retinal basement membrane, leading to arrested astrocyte migration and reduced angiogenesis. Using genetic deletion and time-lapse imaging, we show that retinal astrocytes require neuronal-derived PDGF as a chemoattractive cue and the retinal basement membrane as a migratory substrate. Genetic ablation of heparan sulfates does not produce the same defects as GAG null mutants. In contrast, enzymatic removal of heparan sulfates and chondroitin sulfates together inhibits de novo laminin network assembly. These results indicate that both heparan and chondroitin sulfate proteoglycans participate in retinal basement membrane assembly, thus promoting astrocyte migration and angiogenesis.

SUBMITTER: Tao C

PROVIDER: S-EPMC5129871 | biostudies-literature | 2016 Nov

REPOSITORIES: biostudies-literature

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Retinal Proteoglycans Act as Cellular Receptors for Basement Membrane Assembly to Control Astrocyte Migration and Angiogenesis.

Tao Chenqi C Zhang Xin X

Cell reports 20161101 7

The basement membrane is crucial for cell polarity, adhesion, and motility, but how it is assembled on the cell surface remains unclear. Here, we find that ablation of glycosaminoglycan (GAG) side chains of proteoglycans in the neuroretina disrupts the retinal basement membrane, leading to arrested astrocyte migration and reduced angiogenesis. Using genetic deletion and time-lapse imaging, we show that retinal astrocytes require neuronal-derived PDGF as a chemoattractive cue and the retinal base ...[more]

PMID: 27829154

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Project description:Human papillomaviruses (HPVs) are nonenveloped double-stranded DNA viruses that utilize heparan sulfate proteoglycans (HSPGs) as initial attachment factors prior to cell entry and infection. While extensively characterized, the selective interaction between HPV and HSPGs is generally studied using standard in vitro conditions, which fail to account for the effects that media additives, such as fetal bovine serum (FBS), can have on viral binding. As environmental conditions and growth factors associated with wound healing are thought to play a role in natural HPV infection, we sought to investigate the effects that serum or platelet extracts could have on the binding and infectivity of HPV. Here, we demonstrate that high concentrations of FBS and human serum greatly inhibit HPV16 binding, and that for FBS, this effect results from the obstruction of cell surface HSPGs by serum-derived heparin-binding proteins (HBPs). Surprisingly, we found that under these conditions, HPV particles utilize 6O-sulfated chondroitin sulfate proteoglycans (CSPGs) as initial binding receptors prior to infection. These findings were corroborated by small interfering RNA (siRNA)-mediated knockdown experiments, as well as through a cancer cell line screen, where we identified a strong association between viral binding in high serum and the expression of chondroitin sulfate biosynthesis genes. Furthermore, HPV binding in the presence of human platelet lysate also demonstrated an increased dependance on CSPGs, suggesting a possible role for these receptor proteoglycans in active wound healing environments. Overall, this work highlights the significant influence that serum/platelet factors can have on virus binding and identifies CSPGs as alternative cell attachment receptors for HPV. IMPORTANCE Heparan sulfate proteoglycans (HSPGs) have previously been identified as primary attachment factors for the initial binding of human papillomaviruses (HPVs) prior to infection. Here, we demonstrate that in vitro, HPV binding to HSPGs is strongly dependent on the surrounding experimental conditions, including the concentration of fetal bovine serum (FBS). We found that high concentrations of FBS can block HSPG-binding sites and cause a dependence on 6O-sulfated chondroitin sulfate proteoglycans (CSPGs) as alternative initial viral receptors. Further, we demonstrate that use of a human-derived alternative to FBS, human platelet lysate, also occludes HSPG-dependent binding, causing a shift toward CSPGs for viral attachment. As HPV infection of basal epithelial cells is thought to occur at sites of microtrauma with exposure to high serum levels and platelet factors, these unexpected findings highlight a possible role for CSPGs as important cellular receptors for the binding and infectivity of HPV in vivo.

Dataset Information

Retinal Proteoglycans Act as Cellular Receptors for Basement Membrane Assembly to Control Astrocyte Migration and Angiogenesis.

Publications

Retinal Proteoglycans Act as Cellular Receptors for Basement Membrane Assembly to Control Astrocyte Migration and Angiogenesis.

Similar Datasets

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