Binding of the Fap2 Protein of Fusobacterium nucleatum to Human Inhibitory Receptor TIGIT Protects Tumors from Immune Cell Attack

Gur, Chamutal; Ibrahim, Yara; Isaacson, Batya; Yamin, Rachel; Abed, Jawad; Gamliel, Moriya; Enk, Jonatan; Bar-On, Yotam; Stanietsky-Kaynan, Noah; Coppenhagen-Glazer, Shunit; Shussman, Noam; Almogy, Gideon; Cuapio, Angélica; Hofer, Erhard; Mevorach, Dror; Tabib, Adi; Ortenberg, Rona; Markel, Gal; Miklić, Karmela; Jonjić, Stipan; Brennan, Caitlin A.; Garrett, Wendy S.; Bachrach, Gilad; Mandelboim, Ofer

doi:10.1016/j.immuni.2015.01.010

Cited by 1,004 publications

(872 citation statements)

References 32 publications

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“…Pioneering work by the Han lab utilized the animal model (described above) to demonstrate that the protein FadA is required for F. nucleatum localization to and proliferation in the placenta and its subsequent invasion into amniotic fluid and fetal tissue (Ikegami et al 2009). More recently, the adhesin Fap2 has also been shown to be important for bacterial interactions with host carbohydrates, immunomodulation and colonization of the placenta following bloodstream administration (Kaplan et al 2010;Coppenhagen-Glazer et al 2015;Gur et al 2015).…”

Section: Introductionmentioning

confidence: 99%

Discovery and characterization ofde novosialic acid biosynthesis in the phylumFusobacterium

Lewis¹,

Robinson²,

Agarwal³

et al. 2016

Glycobiology

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Sialic acids are nine-carbon backbone carbohydrates found in prominent outermost positions of glycosylated molecules in mammals. Mimicry of sialic acid (N-acetylneuraminic acid, Neu5Ac) enables some pathogenic bacteria to evade host defenses. Fusobacterium nucleatum is a ubiquitous oral bacterium also linked with invasive infections throughout the body. We employed multidisciplinary approaches to test predictions that F. nucleatum engages in de novo synthesis of sialic acids. Here we show that F. nucleatum sbsp. polymorphum ATCC10953 NeuB (putative Neu5Ac synthase) restores Neu5Ac synthesis to an Escherichia coli neuB mutant. Moreover, purified F. nucleatum NeuB participated in synthesis of Neu5Ac from N-acetylmannosamine and phosphoenolpyruvate in vitro. Further studies support the interpretation that F. nucleatum ATCC10953 NeuA encodes a functional CMP-sialic acid synthetase and suggest that it may also contain a C-terminal sialic acid O-acetylesterase. We also performed BLAST queries of F. nucleatum genomes, revealing that only 4/31 strains encode a complete pathway for de novo Neu5Ac synthesis. Biochemical studies including mass spectrometry were consistent with the bioinformatic predictions, showing that F. nucleatum ATCC10953 synthesizes high levels of Neu5Ac, whereas ATCC23726 and ATCC25586 do not express detectable levels above background. While there are a number of examples of sialic acid mimicry in other phyla, these experiments provide the first biochemical and genetic evidence that a member of the phylum Fusobacterium can engage in de novo Neu5Ac synthesis.

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Section: Introductionmentioning

confidence: 99%

Discovery and characterization ofde novosialic acid biosynthesis in the phylumFusobacterium

Lewis¹,

Robinson²,

Agarwal³

et al. 2016

Glycobiology

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“…N atural killer cells are lymphocytes of the innate immune system, which specialize in the eradication of tumor cells and cells infected with viruses or bacteria (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12). A balance of signals derived from activating and inhibitory receptors controls the activity of NK cells (13)(14)(15)(16)(17)(18).…”

mentioning

confidence: 99%

“…Using the Ncr1 gfp/gfp mice, it was revealed that Ncr1 is involved in controlling influenza virus infections (5,22,25), tumor and metastases eradication (6,7,10,24), the development of type I and type II diabetes (11,23,26,27), liver fibrosis (28), and bacterial infections (3,29). In all of these studies, the activity of the Ncr1 gfp/gfp NK cells was impaired in an Ncr1-dependent manner.…”

mentioning

confidence: 99%

Expression, Function, and Molecular Properties of the Killer Receptor Ncr1-Noé

Glasner¹,

Šimić

Miklić

et al. 2015

The Journal of Immunology

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NK cells kill various cells using activating receptors, such as the natural cytotoxicity receptors (NCRs). NKp46 is a major NCR and is the only NCR expressed in mice (denoted Ncr1). Using Ncr1-deficient mice (Ncr1gfp/pfp) we demonstrated that Ncr1 controls various pathologies, and that in its absence Ncr1-related functions are impaired. In 2012, another Ncr1-related mouse was generated, named Noé, in which a random mutation, W32R, in position 32, impaired the Ncr1-Noé cell surface expression. Interestingly, in the Noé mice, Ncr1-dependent deficiencies were not observed. Additionally, the Noé-NK cells were hyperactivated, probably due to increased Helios expression, and the Noé mice demonstrate increased clearance of influenza and murine CMV. In contrast, in the Ncr1gfp/pfp mice infection with influenza was lethal and we show in the present study no difference in murine CMV infection between Ncr1gfp/pfp and wild-type (WT) mice. Because the foremost difference between the Noé and Ncr1gfp/gfp mice is the presence of a mutated Ncr1-Noé protein, we studied its properties. We show that Ncr1-Noé and various other Ncr1 mutants in position 32 can be expressed on the surface, albeit slowly and unstably, and that ligand recognition and function of the various Ncr1-Noé is similar to the WT Ncr1. We further show that the glycosylation pattern of Ncr1-Noé is aberrant, that the Ncr1-Noé proteins accumulate in the endoplasmic reticulum, and that the expression of Ncr1-Noé proteins, but not WT Ncr1, leads to increased Helios expression. Thus, we suggest that the NK hyperactivated phenotype observed in the Noé mice might result from the presence of the Ncr1-Noé protein.

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“…So far, evidence suggests that fusobacteria colonize adenomas or preexisting tumors rather than driving tumor initiation. [8][9][10] It will be interesting to investigate whether other tumor promoting bacteria interact with TIGIT. It also remains to be determined whether blocking the ability of fusobacteria to activate TIGIT will improve tumor control by the host's immunity.…”

Section: Prospectivementioning

confidence: 99%

“…1). 8 Thus, a bacterium-dependent, tumor immune evasion mechanism in which tumors exploit the Fap2 protein of F. nucleatum to inhibit immune cell activity via TIGIT was revealed.…”

mentioning

confidence: 99%

“Messieurs, c'est les microbes qui auront le dernier mot”: Gentlemen, it is the microbes who have the last word (Louis Pasteur)—Fusobacterium nucleatumprotect tumors from killing by immune cells

2015

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Binding of the Fap2 Protein of Fusobacterium nucleatum to Human Inhibitory Receptor TIGIT Protects Tumors from Immune Cell Attack

Cited by 1,004 publications

References 32 publications

Discovery and characterization ofde novosialic acid biosynthesis in the phylumFusobacterium

Discovery and characterization ofde novosialic acid biosynthesis in the phylumFusobacterium

Expression, Function, and Molecular Properties of the Killer Receptor Ncr1-Noé

“Messieurs, c'est les microbes qui auront le dernier mot”: Gentlemen, it is the microbes who have the last word (Louis Pasteur)—Fusobacterium nucleatumprotect tumors from killing by immune cells

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