Dataset Information

Nidogen-1 is a novel extracellular ligand for the NKp44 activating receptor

ABSTRACT: The release of soluble ligands of activating Natural Killer (NK) cell receptors may represent a regulatory mechanism of NK cell function both in physiologic and in pathologic conditions. Here, we identified the extracellular matrix protein Nidogen-1 (NID1) as a ligand of NKp44, an important activating receptor expressed by activated NK cells. When released as soluble molecule, NID1 can regulate NK cell function by modulating NKp44-induced IFN-γ production or cytotoxicity. We also show that NID1 may be present at the cell surface. In this form or when bound to a solid support (bNID1), NID1 failed to induce NK cell cytotoxicity or cytokine release. However, analysis by mass spectrometry revealed that exposure to bNID1 can induce relevant changes in the proteomic profiles suggesting an effect on different, biological processes of human NK cells.

INSTRUMENT(S): Orbitrap Fusion

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Blood, Mature Natural Killer Cell

SUBMITTER: Chiara Lavarello

LAB HEAD: Andrea Petretto

PROVIDER: PXD008252 | Pride | 2018-10-22

REPOSITORIES: Pride

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			Action	DRS
	Cantoni_0617_10T_149_Library_029.raw	Raw
	Cantoni_0617_10_113_114_Library_032.raw	Raw
	Cantoni_0617_11T_149_Library_036.raw	Raw
	Cantoni_0617_11_113_114_Library_039.raw	Raw
	Cantoni_0617_12T_149_Library_043.raw	Raw

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Nidogen-1 is a novel extracellular ligand for the NKp44 activating receptor.

Gaggero Silvia S Bruschi Maurizio M Petretto Andrea A Parodi Monica M Del Zotto Genny G Lavarello Chiara C Prato Carola C Santucci Laura L Barbuto Alessandra A Bottino Cristina C Candiano Giovanni G Moretta Alessandro A Vitale Massimo M Moretta Lorenzo L Cantoni Claudia C

Oncoimmunology 20180711 9

The release of soluble ligands of activating Natural Killer (NK) cell receptors may represent a regulatory mechanism of NK cell function both in physiologic and in pathologic conditions. Here, we identified the extracellular matrix protein Nidogen-1 (NID1) as a ligand of NKp44, an important activating receptor expressed by activated NK cells. When released as soluble molecule, NID1 regulates NK cell function by modulating NKp44-induced IFN-γ production or cytotoxicity. In particular, it also mod ...[more]

PMID: 30228939

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Project description:Background: In previous studies we showed that IL-27 shares several effects with IFN-γ in human cancer cells. To identify novel extracellular mediators, potentially involved in epithelial ovarian cancer (EOC) biology, we analyzed the effect of IL-27 or IFN-γ on the secretome of EOC cells in culture. Methods: The secretome of cytokine-treated or untreated SKOV3 cells was analyzed by nano-UHPLC-MS/MS and eluting peptides by an Orbitrap Fusion Tribrid mass spectrometer. Extracellular GBP1 was studied by ELISA, immunoprecipitation, GTP-agarose pull-down, and Western blotting. GBP and STAT proteins were analysed on cell lysates by Western blot. GBP1 was transfected using lipofectamine reagent and cell viability measured by MTT assay. Results: IL-27 and IFN-γ modulate the extracellular release of a limited fraction of proteins that were also induced in the whole cell. Among these proteins we focused our attention on GBP1, a guanylate-binding protein and GTPase, which is a mediator of several biological activities of IFNs. Interestingly GBP1, 2, and 5 were induced by cytokine treatment in EOC cells, but only GBP1 was secreted. ELISA and immuno-blotting analyses showed that cytokine-stimulated EOC cells release full-length GBP1 molecule in vitro, through non-classical pathways, not involving microvesicles. Moreover, soluble, full-length GBP1 accumulates in the ascites of most EOC patients, suggesting a potential role of extracellular GBP1 in the tumor environment. EOC cells enriched from ascites showed constitutive tyrosine-phosphorylated STAT1 and STAT3 proteins and GBP1 expression, supporting a role of STAT-activating cytokines in GBP1 induction in vivo. Data from the TCGA dataset of EOC indicate that high GBP1 gene expression correlates with a better overall survival. Accordingly GBP1 transfection reduced SKOV3 cell proliferation, suggesting a potential anti-tumor activity of GBP1. Conclusions: Our data show for the first time that soluble GBP1 is released by cytokine-stimulated EOC cells in vitro and accumulates in EOC patients’ ascites. GBP1 expression may have anti-tumor effects, in EOC, as suggested by TCGA dataset analysis and in vitro transfection experiments. Further studies to identify the biological role of soluble GBP1 in the tumor environment of EOC are warranted.