Complex roles of members of the ADP-ribosyl transferase super family in immune defences: looking beyond PARP1.

ADP ribosylation has been recently recognised as an important posttranslational modification regulating numerous cellular processes. This enzymatic activity is shared by two major families of enzymes, the extracellular ADP-ribosyl-transferases, or ecto-ARTS and the poly-ADP-ribosyltranferases, whose denomination derives from the capacity of its founding member, PARP1, to synthesise large linear or branched polymers of ADP-ribose on target proteins. This latter post-translational modification has recently attracted much interest based on its role in the cellular response to genotoxic and oxidative stress. Accordingly, a series of PARP-specific pharmacological inhibitors have demonstrated cell survival and anti-inflammatory properties in vivo, promoting a renewed interest in the potential immunoregulatory role of this gene family. More recently, the role of ADP-ribosylation in regulating several aspects of intracellular signalling and gene transcription has been uncovered, in particular within cells of the immune system, revealing the potential immunomodulatory role of several members of this family in addition to PARP1. We review herein the experimental evidence illustrating the complex role played by this gene family in regulating multiple aspects of the immune response, including cell survival, cytokine gene transcription and antiviral innate defences. In particular, the unexpected potential anti-inflammatory role of members of this family (including in particular PARP5a, 5b and PARP14) will be briefly discussed, raising some concern on the use of pan-specific PARP inhibitors to treat chronic inflammatory diseases.