Pleiotrophin inhibits HIV infection by binding the cell surface-expressed nucleolin

UPR 2228 CNRS, UFR Biomédicale des Saints-Pères, Paris, France.
FEBS Journal (Impact Factor: 3.99). 10/2005; 272(18):4646-59. DOI: 10.1111/j.1742-4658.2005.04870.x
Source: PubMed

ABSTRACT The growth factor pleiotrophin (PTN) has been reported to bind heparan sulfate and nucleolin, two components of the cell surface implicated in the attachment of HIV-1 particles to cells. Here we show that PTN inhibits HIV-1 infection by its capacity to inhibit HIV-1 particle attachment to the surface of permissive cells. The beta-sheet domains of PTN appear to be implicated in this inhibitory effect on the HIV infection, in particular the domain containing amino acids 60-110. PTN binding to the cell surface is mediated by high and low affinity binding sites. Other inhibitors of HIV attachment known to bind specifically surface expressed nucleolin, such as the pseudopeptide HB-19 and the cytokine midkine prevent the binding of PTN to its low affinity-binding site. Confocal immunofluorescence laser microscopy revealed that the cross-linking of surface-bound PTN with a specific antibody results in the clustering of cell surface-expressed nucleolin and the colocalization of both PTN and nucleolin signals. Following its binding to surface-nucleolin, PTN is internalized by a temperature sensitive mechanism, a process which is inhibited by HB-19 and is independent of heparan and chondroitin sulfate proteoglycans. Nevertheless, proteoglycans might play a role in the concentration of PTN on the cell surface for a more efficient interaction with nucleolin. Our results demonstrate for the first time that PTN inhibits HIV infection and suggest that the cell surface-expressed nucleolin is a low affinity receptor for PTN binding to cells and it is also implicated in PTN entry into cells by an active process.

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Available from: Elias Said, Oct 13, 2014
    • "Recognition of early apoptotic cells by cell surface NCL on monocytes and macrophages [139] [140] MK Temperature-dependent active internalization process / Inhibition of HIV-1 infection [42] [43] [142] HGF Regulatory interplay between stromal and epithelial cells within the prostate [102] VEGF VEGF 165 -induced endothelial cell migration [106] [122] PTN Temperature-dependent active internalization process / Inhibition of HIV-1 infection / PTNinduced endothelial cell migration [143] [116] Acharan sulfate Anti-tumor activity in vitro and in vivo [101] ADAMTS-2 Anti-angiogenic action in vitro and in vivo [147] Lactoferrin Inhibition of the proliferation of cancerous mammary gland epithelial cells / Potent antiviral activity against HIV and CMV [44] ES Transportation of ES in the nucleus / Antiangiogenic and anti-tumor activities of ES in vivo / Anti-lymphangiogenic activities of ES [98, 148] scuPA Transportation of scuPA in the nucleus / Induction of α-SMA expression in human fibroblasts [40] Tumor-homing peptide F3 "
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    • "To test the involvement of cell-surface nucleolin in EPEC infection, we used the cytokine midkine (MK) and the growth factor pleiotrophin (PTN), which bind cell-surface nucleolin (Said et al., 2005; Take et al., 1994) and inhibit HIV attachment to host cells (Hovanessian, 2006). We assessed whether MK or PTM exposure to Caco-2 cells would interfere with various aspects of the EPEC infection process including (i) disruption of transepithelial electrical resistance (TER; a measure of epithelial barrier function), (ii) microvilli effacement, (iii) pedestal formation and (iv) Fig. 2. EPEC sequesters EGFP-nucleolin into its microcolonies. "
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