HIV-1 p17 Matrix Protein Interacts with Heparan Sulfate Side Chain of CD44v3, Syndecan-2, and Syndecan-4 Proteoglycans Expressed on Human Activated CD4+ T Cells Affecting Tumor Necrosis Factor α and Interleukin 2 Production

Francesco, Maria Antonia De; Baronio, Manuela; Poiesi, Claudio

doi:10.1074/jbc.m110.191270

Cited by 18 publications

(24 citation statements)

References 48 publications

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“…HSPGs were found to critically regulate angiogenesis by facilitating cell-surface binding of various proangiogenic molecules (27). Recent data showed that p17 is a heparin/heparan sulfate-binding protein (28). Therefore, we assessed whether p17 binding to HSPGs expressed on HUVECs could play a part in p17-induced capillary-like structure formation.…”

Section: Resultsmentioning

confidence: 99%

HIV-1 matrix protein p17 promotes angiogenesis via chemokine receptors CXCR1 and CXCR2

Caccuri¹,

Giagulli²,

Bugatti³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

106

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Vascular diseases supported by aberrant angiogenesis have increased incidence in HIV-1-infected patients. Several data suggest that endothelium dysfunction relies on action of HIV-1 proteins rather than on a direct effect of the virus itself. The HIV-1 matrix protein p17 is known to deregulate the biological activity of different immune cells. Recently, p17 was found to mimic IL-8 chemokine activity by binding to the IL-8 receptor CXCR1. Here we show that p17 binds with high affinity to CXCR2, a CXCR1-related receptor, and promotes the formation of capillary-like structures on human endothelial cells (ECs) by interacting with both CXCR1 and CXCR2 expressed on the EC surface. ERK signaling via Akt was defined as the pathway responsible for p17-induced tube formation. Ex vivo and in vivo experimental models confirmed the provasculogenic activity of p17, which was comparable to that induced by VEGF-A. The hypothesis of a major role for p17 in HIV-1-induced aberrant angiogenesis is enforced by the finding that p17 is detected, as a single protein, in blood vessels of HIV-1-patients and in particular in the nucleus of ECs. Localization of p17 in the nucleus of ECs was evidenced also in in vitro experiments, suggesting the internalization of exogenous p17 in ECs by mechanisms of receptormediated endocytosis. Recognizing p17 interaction with CXCR1 and CXCR2 as the key event in sustaining EC aberrant angiogenesis could help us to identify new treatment strategies in combating AIDSrelated vascular diseases. extracellular viral proteins | virokine | Akt-mediated ERK pathway | vasculogenic assays | surface plasmon resonance A ngiogenesis is a physiological process requiring growth of new blood vessels from preexisting vessels. This process involves coordinated endothelial cell (EC) proliferation, invasion, migration, and tube formation (1). When new vessels are required, proangiogenic factors are produced, whereas restoration of physiological conditions is achieved by producing inhibitors of angiogenesis and vessel stabilization factors. Breakdown of the tight regulated angiogenic balance leads to dysfunctional endothelium, abnormal angiogenesis, and vascular diseases.

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Section: Resultsmentioning

confidence: 99%

HIV-1 matrix protein p17 promotes angiogenesis via chemokine receptors CXCR1 and CXCR2

Caccuri¹,

Giagulli²,

Bugatti³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

106

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“…It is worth noting that several authors demonstrated the binding of p17 to heparan sulfate proteoglycans. 29,30 Such interaction, as already demonstrated for many heparin-binding chemokines, 31 may allow a better presentation of p17 to CXCR1 and CXCR2 setting up synergistic and cooperative interactions leading to increased concentrations of the viral protein at the LN-LEC surface.…”

Section: Discussionmentioning

confidence: 99%

HIV-1 Matrix Protein p17 Promotes Lymphangiogenesis and Activates the Endothelin-1/Endothelin B Receptor Axis

Caccuri

Rueckert

Giagulli

et al. 2014

ATVB

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Objective— AIDS-related lymphomas are high grade and aggressively metastatic with poor prognosis. Lymphangiogenesis is essential in supporting proliferation and survival of lymphoma, as well as tumor dissemination. Data suggest that aberrant lymphangiogenesis relies on action of HIV-1 proteins rather than on a direct effect of the virus itself. HIV-1 matrix protein p17 was found to accumulate and persist in lymph nodes of patients even under highly active antiretroviral therapy. Because p17 was recently found to exert a potent proangiogenic activity by interacting with chemokine (C-X-C motif) receptors 1 and 2, we tested the prolymphangiogenic activity of the viral protein. Approach and Results— Human primary lymph node–derived lymphatic endothelial cells were used to perform capillary-like structure formation, wound healing, spheroids, and Western blot assays after stimulation with or without p17. Here, we show that p17 promotes lymphangiogenesis by binding to chemokine (C-X-C motif) receptor-1 and chemokine (C-X-C motif) receptor-2 expressed on lymph node–derived lymphatic endothelial cells and activating the Akt/extracellular signal–regulated kinase signaling pathway. In particular, it was found to induce capillary-like structure formation, sprout formation from spheroids, and increase lymph node–derived lymphatic endothelial cells motility. The p17 lymphangiogenic activity was, in part, sustained by activation of the endothelin-1/endothelin receptor B axis. A Matrigel plug assay showed that p17 was able to promote the outgrowth of lymphatic vessels in vivo, demonstrating that p17 directly regulates lymphatic vessel formation. Conclusions— Our results suggest that p17 may generate a prolymphangiogenic microenvironment and plays a role in predisposing the lymph node to lymphoma growth and metastasis. This finding offers new opportunities to identify treatment strategies in combating AIDS-related lymphomas.

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“…p17 binds heparin with an affinity (K d ϭ 190 nM) that is similar to that of gp120 (K d ϭ 200 -600 nM) and only three times lower than that of Tat (K d ϭ 30 -60 nM), two HIV proteins that exploit HSPGs to mediate important biological effects (see Introduction). On the other hand, p17 binds to HSPGs on leukocytes, and although no formal demonstration has been provided, this interaction has been tentatively associated to the modulation of inflammatory cytokines expression (14). Even if the possibility that p17-HSPGs interaction directly induces some biological activity in the cell cannot be ruled out, it is likely that HSPGs may instead act as typical co-receptors, which, by binding p17, cause its conformational modifications/oligomerization that, in turn, ameliorate its binding to signaling receptors such as CXCR1.…”

Section: Discussionmentioning

confidence: 99%

“…Both HSPGs and CXCR1 have been implicated in p17-induced activation of leukocytes (11,14). Because K5NOSH inhibits the interaction of p17 with both heparin and CXCR1, we evaluated its capacity to prevent p17-dependent migration of monocytes.…”

Section: Hiv-1 Protein P17 and Heparinmentioning

confidence: 99%

“…Extracellular p17 deregulates the functions of many immune cells involved in AIDS pathogenesis (7): it reduces MIP-1␣ secretion in activated monocytes (8), induces activated T cell proliferation enhancing HIV replication (9), increases IFN-␥ and TNF-␣ production decreasing the ability of IL-4 to down-regulate the secretion of such cytokines in activated peripheral blood mononuclear and natural killer cells (7,10). Three distinct cellular receptors for p17 have been identified: the chemokine receptors CXCR1 and CXCR2, which mediate p17-driven monocyte migration (11) and endothelial cells proangiogenic activation (12), respectively, and heparan sulfate proteoglycans (HSPGs), 2 tentatively associated to p17-driven cytokine up-regulation in CD4ϩ lymphocytes (13,14).…”

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confidence: 99%

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Molecular Interaction Studies of HIV-1 Matrix Protein p17 and Heparin

Bugatti

Giagulli

Urbinati

et al. 2013

Journal of Biological Chemistry

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Background: HIV-1 p17 binds heparin and heparan sulfate proteoglycans of the cell surface. Results: Heparin/p17 interaction occurs through heparin sulfate groups and a linear basic motif of p17 N terminus, also involved in p17/CXCR1 interaction. Conclusion: Targeting the basic motif inhibits p17-receptors interaction and consequent biological activities. Significance: Heparin-like molecules represent template for the development of new treatments of p17-dependent/AIDSassociated pathologies.

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HIV-1 p17 Matrix Protein Interacts with Heparan Sulfate Side Chain of CD44v3, Syndecan-2, and Syndecan-4 Proteoglycans Expressed on Human Activated CD4+ T Cells Affecting Tumor Necrosis Factor α and Interleukin 2 Production

Abstract: HIV-1 p17 contains C-and N-terminal sequences with positively charged residues and a consensus cluster for heparin binding. We have previously demonstrated by affinity chromatography that HIV-1 p17 binds strongly to heparin-agarose at physiological pH and to human activated CD4

Cited by 18 publications

References 48 publications

HIV-1 matrix protein p17 promotes angiogenesis via chemokine receptors CXCR1 and CXCR2

HIV-1 matrix protein p17 promotes angiogenesis via chemokine receptors CXCR1 and CXCR2

HIV-1 Matrix Protein p17 Promotes Lymphangiogenesis and Activates the Endothelin-1/Endothelin B Receptor Axis

Molecular Interaction Studies of HIV-1 Matrix Protein p17 and Heparin

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