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  • Loss of HIF-1α in natural killer cells inhibits tumour growth by stimulating non-productive angiogenesis.

    20 novembre, par Krzywinska E, Kantari-Mimoun C, Kerdiles Y, Sobecki M, Isagawa T, Gotthardt D, Castells M, Haubold J, Millien C, Viel T, Tavitian B, Takeda N, Fandrey J, Vivier E, Sexl V, Stockmann C
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    Loss of HIF-1α in natural killer cells inhibits tumour growth by stimulating non-productive angiogenesis.

    Nat Commun. 2017 Nov 17;8(1):1597

    Authors: Krzywinska E, Kantari-Mimoun C, Kerdiles Y, Sobecki M, Isagawa T, Gotthardt D, Castells M, Haubold J, Millien C, Viel T, Tavitian B, Takeda N, Fandrey J, Vivier E, Sexl V, Stockmann C

    Abstract
    Productive angiogenesis, a prerequisite for tumour growth, depends on the balanced release of angiogenic and angiostatic factors by different cell types within hypoxic tumours. Natural killer (NK) cells kill cancer cells and infiltrate hypoxic tumour areas. Cellular adaptation to low oxygen is mediated by Hypoxia-inducible factors (HIFs). We found that deletion of HIF-1α in NK cells inhibited tumour growth despite impaired tumour cell killing. Tumours developing in these conditions were characterised by a high-density network of immature vessels, severe haemorrhage, increased hypoxia, and facilitated metastasis due to non-productive angiogenesis. Loss of HIF-1α in NK cells increased the bioavailability of the major angiogenic cytokine vascular endothelial growth factor (VEGF) by decreasing the infiltration of NK cells that express angiostatic soluble VEGFR-1. In summary, this identifies the hypoxic response in NK cells as an inhibitor of VEGF-driven angiogenesis, yet, this promotes tumour growth by allowing the formation of functionally improved vessels.

    PMID: 29150606 [PubMed - in process]

  • Biogenesis of the bacterial cbb3 cytochrome c oxidase : active subcomplexes support a sequential assembly model.

    20 novembre, par Durand A, Bourbon ML, Steunou AS, Khalfaoui-Hassani B, Legrand C, Guitton A, Astier C, Ouchane S
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    Biogenesis of the bacterial cbb3 cytochrome c oxidase: active subcomplexes support a sequential assembly model.

    J Biol Chem. 2017 Nov 17;:

    Authors: Durand A, Bourbon ML, Steunou AS, Khalfaoui-Hassani B, Legrand C, Guitton A, Astier C, Ouchane S

    Abstract
    The cbb3 oxidase has a high affinity for oxygen and is required for growth of bacteria, including pathogens, in oxygen-limited environments. However, the assembly of this oxidase is poorly understood. Most cbb3 are composed of four subunits: the catalytic CcoN subunit, the two cytochromes c subunits (CcoO and CcoP) involved in electron transfer and the small CcoQ subunit with an unclear function. Here, we address the role of these four subunits in cbb3 biogenesis in the purple bacterium Rubrivivax gelatinosus Analyses of membrane proteins from different mutants revealed the presence of active CcoNQO and CcoNO subcomplexes and also showed that the CcoP subunit is not essential for their assembly. However, CcoP was required for the oxygen reduction activity in the absence of CcoQ. We also found that CcoQ is dispensable for forming an active CcoNOP subcomplex in membranes. CcoNOP exhibited oxygen reductase activity, indicating that the cofactors (hemes b and copper for CcoN, cytochromes c for CcoO and CcoP) were present within the subunits. Finally, we discovered the presence of a CcoNQ subcomplex and showed that CcoN is the required anchor for the assembly of the full CcoNQOP complex. On the basis of these findings, we propose a sequential assembly model in which the CcoQ subunit is required for the early maturation step: CcoQ first associates with CcoN before the CcoNQ-CcoO interaction. CcoP associates to CcoNQO subcomplex in the late maturation step and once the CcoNQOP complex is fully formed, CcoQ is released for degradation by the FtsH protease. This model could be conserved in other bacteria including the pathogenic bacteria lacking the assembly factor CcoH as in R. gelatinosus.

    PMID: 29150446 [PubMed - as supplied by publisher]

  • SAFER, an Analysis Method of Quantitative Proteomic Data, Reveals New Interactors of the C. elegans Autophagic Protein LGG-1.

    8 novembre, par Yi Z, Manil-Ségalen M, Sago L, Glatigny A, Redeker V, Legouis R, Mucchielli-Giorgi MH
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    SAFER, an Analysis Method of Quantitative Proteomic Data, Reveals New Interactors of the C. elegans Autophagic Protein LGG-1.

    J Proteome Res. 2016 May 06;15(5):1515-23

    Authors: Yi Z, Manil-Ségalen M, Sago L, Glatigny A, Redeker V, Legouis R, Mucchielli-Giorgi MH

    Abstract
    Affinity purifications followed by mass spectrometric analysis are used to identify protein-protein interactions. Because quantitative proteomic data are noisy, it is necessary to develop statistical methods to eliminate false-positives and identify true partners. We present here a novel approach for filtering false interactors, named "SAFER" for mass Spectrometry data Analysis by Filtering of Experimental Replicates, which is based on the reproducibility of the replicates and the fold-change of the protein intensities between bait and control. To identify regulators or targets of autophagy, we characterized the interactors of LGG1, a ubiquitin-like protein involved in autophagosome formation in C. elegans. LGG-1 partners were purified by affinity, analyzed by nanoLC-MS/MS mass spectrometry, and quantified by a label-free proteomic approach based on the mass spectrometric signal intensity of peptide precursor ions. Because the selection of confident interactions depends on the method used for statistical analysis, we compared SAFER with several statistical tests and different scoring algorithms on this set of data. We show that SAFER recovers high-confidence interactors that have been ignored by the other methods and identified new candidates involved in the autophagy process. We further validated our method on a public data set and conclude that SAFER notably improves the identification of protein interactors.

    PMID: 26999449 [PubMed - indexed for MEDLINE]

  • Peptide deformylases from Vibrio parahaemolyticus phage and bacteria display similar deformylase activity and inhibitor binding clefts.

    5 novembre, par Grzela R, Nusbaum J, Fieulaine S, Lavecchia F, Desmadril M, Nhiri N, Van Dorsselaer A, Cianferani S, Jacquet E, Meinnel T, Giglione C
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    Peptide deformylases from Vibrio parahaemolyticus phage and bacteria display similar deformylase activity and inhibitor binding clefts.

    Biochim Biophys Acta. 2017 Oct 31;:

    Authors: Grzela R, Nusbaum J, Fieulaine S, Lavecchia F, Desmadril M, Nhiri N, Van Dorsselaer A, Cianferani S, Jacquet E, Meinnel T, Giglione C

    Abstract
    Unexpected peptide deformylase (PDF) genes were recently retrieved in numerous marine phage genomes. While various hypotheses dealing with the occurrence of these intriguing sequences have been made, no further characterization and functional studies have been described thus far. In this study, we characterize the bacteriophage Vp16 PDF enzyme, as representative member of the newly identified C-terminally truncated viral PDFs. We show here that conditions classically used for bacterial PDFs lead to an enzyme exhibiting weak activity. Nonetheless, our integrated biophysical and biochemical approaches reveal specific effects of pH and metals on Vp16 PDF stability and activity. A novel purification protocol taking in account these data allowed strong improvement of Vp16 specific activity to values similar to those of bacterial PDFs. We next show that Vp16PDF is as sensitive to the natural inhibitor compound of PDFs, actinonin, as bacterial PDFs. Comparison of the 3D structures of Vp16 and E. coli PDFs bound to actinonin also reveals that both PDFs display identical substrate binding mode. We conclude that bacteriophage Vp16 PDF protein has functional peptide deformylase activity and we suggest that encoded phage PDFs might be important for viral fitness.

    PMID: 29101077 [PubMed - as supplied by publisher]

  • Spectral and 3D model studies of the interaction of orphan human cytochrome P450 2U1 with substrates and ligands.

    4 novembre, par Dhers L, Pietrancosta N, Ducassou L, Ramassamy B, Dairou J, Jaouen M, André F, Mansuy D, Boucher JL
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    Spectral and 3D model studies of the interaction of orphan human cytochrome P450 2U1 with substrates and ligands.

    Biochim Biophys Acta. 2017 01;1861(1 Pt A):3144-3153

    Authors: Dhers L, Pietrancosta N, Ducassou L, Ramassamy B, Dairou J, Jaouen M, André F, Mansuy D, Boucher JL

    Abstract
    BACKGROUND: Cytochrome P450 2U1 (CYP2U1) has been identified from the human genome and is highly conserved in the living kingdom. It is considered as an "orphan" protein as few data are available on its physiological function(s) and spectral characteristics. Its only known substrates reported so far are unsaturated fatty acids such as arachidonic acid (AA), and, more recently, N-arachidonoylserotonin (AS) and some xenobiotics related to debrisoquine (Deb) and terfenadine.
    METHODS: We have expressed CYP2U1 in E. coli and performed UV-vis and EPR spectroscopy experiments with purified CYP2U1 alone and in the presence of substrates and imidazole and pyridine derivatives. Docking experiments using a 3D homology model of CYP2U1 were done to explain the observed spectroscopic data and the different regioselectivities of the oxidations of AA and AS.
    RESULTS: The UV-vis and EPR spectra of native recombinant human CYP2U1 revealed a predominant low-spin hexacoordinate Fe(III) state. Imidazole (Im) derivatives, such as miconazole, acted as Fe(III) ligands, contrary to ketoconazole, whereas the previously described substrates AS and Deb led to "reverse type I" difference UV-vis spectra. These data, as well as the different regioselectivities of AA and AS oxidations, were supported by docking experiments performed on our previously reported CYP2U1 3D model.
    MAJOR CONCLUSION AND GENERAL SIGNIFICANCE: Our study describes for the first time the mode of interaction of several Fe(III)-heme ligands and substrates with the active site of CYP2U1 on the basis of spectroscopic and molecular docking data. The good agreement between these data validates the used CYP2U1 3D model which should help the design of new substrates or inhibitors of this orphan CYP.

    PMID: 27456766 [PubMed - indexed for MEDLINE]

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