Ecto-ADP-Ribosyltransferases (ARTs): Emerging Actors in Cell Communication and Signaling

Abstract

Mammalian ecto ADP-ribosyltransferases (ARTs) constitute a family of structurally related proteins expressed on the cell surface or secreted in the extracellular compartment. Using NAD+ as substrate, they transfer ADP-ribose groups onto target proteins. In contrast to intracellular poly(ADP-ribosyl)transferases (PARPs), these enzymes transfer a single ADPR and are thus mono-ARTs. Five paralogs (ART1-5) have been cloned but only four of them are expressed in human due to a defective ART2 gene, and six in the mouse as the result of ART2 gene duplication. The recent determination of the crystal structure of rat ART2 reveals homologies with bacterial ART toxins and provides a molecular basis for understanding the specificity of ARTs for their targets. A combination of different technological approaches reveals that ecto-ARTs are expressed in different tissues with privileged sites such as heart and skeletal muscles for ART1, T lymphocytes for ART2 or testis for ART5. It also indicates that ART expression is highly regulated. ADP-ribosylation of target proteins on cell surfaces or circulating in body fluids leads to reversible post-translational modifications which can inhibit the targets, as known for bacterial ARTs, or activate them, as in the crosstalk between mouse ART2 and the cytolytic P2X7 receptor on T lymphocytes. ART activity in the extracellular compartment provides sophisticated regulatory mechanisms for cell communication. This designates ecto-ARTs as new candidates for drug targeting.

Combining affinity purification by ADP-ribose-binding macro domains with mass spectrometry to define the mammalian ADP-ribosyl proteome

“…M ono-ADP-ribosylation is a posttranslational modification that is catalyzed by bacterial toxins and eukaryotic enzymes that transfer the ADP-ribose moiety from ␤-NAD ϩ to various cellular acceptor proteins (1)(2)(3). Several bacterial ADPribosyltransferases (ARTs) are potent virulence factors.…”

“…Importantly, endogenous, toxin-related ARTs have also been found in mammals, where they appear to mediate both intracellular and extracellular reactions (1)(2)(3). The latter are due to glycosylphosphatidylinositol-anchored or secreted enzymes that can modify either soluble or plasma-membrane-associated protein targets, including the P 2 X 7 purinergic receptor, human neutrophil protein 1, and ␣ 7 integrin (13)(14)(15).…”

“…Despite its potential to have crucial roles in the regulation of complex biological processes, including cell signaling and metabolism, membrane trafficking, apoptosis, and gene regulation (2,3,20), protein mono-ADP-ribosylation in intact cells remains little explored. This is mainly because of the difficulties in the isolation of the mono-ADP-ribosylated target proteins, due to a lack of specific tools.…”

NAD+-Consuming Enzymes in the Regulation of Lung Immune Responses

“…All mARTs are linked to the cell surface via a glycosylphosphatidylinositol-anchor, except for ART5, which is a secreted protein [19]. The ART1 and ART2 proteins are the best characterized members of mART family at the genetic, biochemical and cell physiological level [15,20]. As no enzyme activity has yet been demonstrated for ART3 and ART4 [18] and as ART5 functions are not yet known, this review will be focusing on ART1 and ART2 and their potential role in immunity.…”

Characterisation of the R276A gain-of-function mutation in the ectodomain of murine P2X7

“…This posttranslational protein modification, called ADP-ribosylation, is a well-known enzymatic reaction responsible for the deleterious effects of various bacterial toxins, as for instance the agents responsible for diphtheria and cholera. A family of toxin-related ARTs has been discovered and characterised in mammals and has been shown to display a similar conserved protein fold [23,24]. Remarkably, while ADP-ribosylation catalysed by bacterial toxins usually results in the functional inactivation of the target proteins, ADP-ribosylation of P2X7 by ART2.2 on the surface of mouse T lymphocytes results in its activation [14].…”