The orthologue of the "acatalytic" mammalian ART4 in chicken is an arginine-specific mono-ADP-ribosyltransferase

The differentiation of human monocytes into macrophages is influenced by environmental signals. Here we asked in how far nicotinamide (NAM), a vitamin B3 derivative known to play a major role in nicotinamide adenine dinucleotide (NAD)-mediated signaling events, is able to modulate monocyte differentiation into macrophages developed in the presence of granulocyte macrophage colony-stimulating factor (GM-MØ) or macrophage colony-stimulating factor (M-MØ). We found that GM-MØ undergo biochemical, morphological and functional modifications in response to NAM, whereas M-MØ were hardly affected. GM-MØ exposed to NAM acquired an M-MØ-like structure while the LPS-induced production of pro-inflammatory cytokines and COX-derived eicosanoids were down-regulated. In contrast, NAM had no effect on the production of IL-10 or the cytochrome P450-derived eicosanoids. Administration of NAM enhanced intracellular NAD concentrations; however, it did not prevent the LPS-mediated drain on NAD pools. In search of intracellular molecular targets of NAM known to be involved in LPS-induced cytokine and eicosanoid synthesis, we found NF-κB activity to be diminished. In conclusion, our data show that vitamin B3, when present during the differentiation of monocytes into GM-MØ, interferes with biochemical pathways resulting in strongly reduced pro-inflammatory features.

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“…Calculations (ΔΔCt method) were carried out as previously described using GNB2L1 as the reference gene. 23…”

Section: Methodsmentioning

confidence: 99%

Nicotinamide: a vitamin able to shift macrophage differentiation toward macrophages with restricted inflammatory features

et al. 2015

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“…Mouse ART2 (EXE) ADP-ribosylates P2X7 at Arg125 and Arg133 and other proteins at arginine residues (Adriouch et al 2008 ; Koch-Nolte et al 1996 ), rat ART2 (QXE) does not modify target proteins but hydrolyzes NAD + to ADP-ribose and nicotinamide (Haag et al 1995 ). Chicken ART4 (EXE) modifies several proteins at arginine residues; human ART4 (KXE) does not display any detectable ART activity (Glowacki et al 2002 ; Grahnert et al 2008 ). Direct experimental evidence for the importance of the EXE-motif was provided by site directed mutagenesis of ART2 and C3, in which creating or disrupting this motif conferred or destroyed the ability to ADP-ribosylate arginine residues (Hara et al 1996 ; Maehama et al 1996 ; Vogelsgesang and Aktories 2006 ).…”

Section: Arginine-specific Adp-ribosyltransferasesmentioning

confidence: 99%

ADP-ribosylation of arginine

et al. 2010

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Arginine adenosine-5′-diphosphoribosylation (ADP-ribosylation) is an enzyme-catalyzed, potentially reversible posttranslational modification, in which the ADP-ribose moiety is transferred from NAD+ to the guanidino moiety of arginine. At 540 Da, ADP-ribose has the size of approximately five amino acid residues. In contrast to arginine, which, at neutral pH, is positively charged, ADP-ribose carries two negatively charged phosphate moieties. Arginine ADP-ribosylation, thus, causes a notable change in size and chemical property at the ADP-ribosylation site of the target protein. Often, this causes steric interference of the interaction of the target protein with binding partners, e.g. toxin-catalyzed ADP-ribosylation of actin at R177 sterically blocks actin polymerization. In case of the nucleotide-gated P2X7 ion channel, ADP-ribosylation at R125 in the vicinity of the ligand-binding site causes channel gating. Arginine-specific ADP-ribosyltransferases (ARTs) carry a characteristic R-S-EXE motif that distinguishes these enzymes from structurally related enzymes which catalyze ADP-ribosylation of other amino acid side chains, DNA, or small molecules. Arginine-specific ADP-ribosylation can be inhibited by small molecule arginine analogues such as agmatine or meta-iodobenzylguanidine (MIBG), which themselves can serve as targets for arginine-specific ARTs. ADP-ribosylarginine specific hydrolases (ARHs) can restore target protein function by hydrolytic removal of the entire ADP-ribose moiety. In some cases, ADP-ribosylarginine is processed into secondary posttranslational modifications, e.g. phosphoribosylarginine or ornithine. This review summarizes current knowledge on arginine-specific ADP-ribosylation, focussing on the methods available for its detection, its biological consequences, and the enzymes responsible for this modification and its reversal, and discusses future perspectives for research in this field.

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“…Western blot analysis was carried out as described previously [21]. Cells (1.0×10 7 /ml) were suspended in lysis buffer (50 mM Tris/HCl pH 7.5, 150 mM NaCl, 1% (v/v) NP-40, 0.5% (w/v) deoxycholate, 0.1% sodium dodecyl sulfate (SDS; w/v) and cOmplete protease inhibitor cocktail (Roche, Mannheim, Germany)) and sonicated.…”

Section: Western Blot Analysis Of the P2x 4 Receptormentioning

confidence: 99%

Involvement of P2X receptors in the NAD+-induced rise in [Ca2+]i in human monocytes

Grahnert

Klein

Hauschildt

2009

Purinergic Signalling

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In the present study, we show that the extracellular addition of nicotinamide adenine dinucleotide (NAD + ) induces a transient rise in [Ca 2+ ] i in human monocytes caused by an influx of extracellular calcium. The NAD + -induced Ca 2+ response was prevented by adenosine triphosphate (ATP), suggesting the involvement of ATP receptors. Of the two subtypes of ATP receptors (P2X and P2Y), the P2X receptors were considered the most likely candidates. By the use of subtype preferential agonists and antagonists, we identified P2X 1 , P2X 4 , and P2X 7 receptors being engaged in the NAD + -induced rise in [Ca 2+ ] i . Among the P2X receptor subtypes, the P2X 7 receptor is unique in facilitating the induction of nonselective pores that allow entry of ethidium upon stimulation with ATP. In monocytes, opening of P2X 7 receptor-dependent pores strongly depends on specific ionic conditions. Measuring pore formation in response to NAD + , we found that NAD + unlike ATP lacks the ability to induce this pore-forming response. Whereas as little as 100 μM ATP was sufficient to activate the nonselective pore, NAD + at concentrations up to 2 mM had no effect. Taken together, these data indicate that despite similarities in the action of extracellular NAD + and ATP there are nucleotide-specific variations. So far, common and distinct features of the two nucleotides are only beginning to be understood.

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The orthologue of the "acatalytic" mammalian ART4 in chicken is an arginine-specific mono-ADP-ribosyltransferase

Cited by 10 publications

References 37 publications

Nicotinamide: a vitamin able to shift macrophage differentiation toward macrophages with restricted inflammatory features

Nicotinamide: a vitamin able to shift macrophage differentiation toward macrophages with restricted inflammatory features

ADP-ribosylation of arginine

Involvement of P2X receptors in the NAD+-induced rise in [Ca2+]i in human monocytes

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