Beyond DNA repair, the immunological role of PARP‐1 and its siblings

Abstract

SummaryADP-ribosylation is the addition of one or more (up to some hundreds) ADP-ribose moieties to acceptor proteins. There are two major families of enzymes that catalyse this reaction: extracellular ADP-ribosyl-transferases (ARTs), which are bound to the cell membrane by a glycosylphosphatidylinositol anchor or are secreted, and poly(ADP-ribose)-polymerases (PARPs), which are present in the cell nucleus and/or cytoplasm. Recent findings revealed a wide immunological role for ADP-ribosylating enzymes. ARTs, by sensing extracellular NAD concentration, can act as danger detectors. PARP-1, the prototypical representative of the PARP family, known to protect cells from genomic instability, is involved in the development of inflammatory responses and several forms of cell death. PARP-1 also plays a role in adaptive immunity by modulating the ability of dendritic cells to stimulate T cells or by directly affecting the differentiation and functions of T and B cells. Both PARP-1 and PARP-14 (CoaSt6) knockout mice were described to display reduced T helper type 2 cell differentiation and allergic responses. Our recent findings showed that PARP-1 is involved in the differentiation of Foxp3 + regulatory T (Treg) cells, suggesting a role for PARP-1 in tolerance induction. Also ARTs regulate Treg cell homeostasis by promoting Treg cell apoptosis during inflammatory responses. PARP inhibitors ameliorate immune-mediated diseases in several experimental models, including rheumatoid arthritis, colitis, experimental autoimmune encephalomyelitis and allergy. Together these findings show that ADP-ribosylating enzymes, in particular PARP-1, play a pivotal role in the regulation of immune responses and may represent a good target for new therapeutic approaches in immune-mediated diseases.

Interferon-Stimulated Poly(ADP-Ribose) Polymerases Are Potent Inhibitors of Cellular Translation and Virus Replication

“…However, the existence of a large family of PARPs and activation of at least some of its members by type I IFN and directly by viral RNA replication (11) highlight these proteins as important determinants of virus-host interactions and innate immune response development in particular. PARPs are already known to be involved in regulation of a number of critical processes, such as DNA repair, apoptosis, chromatin dynamics, cancer, and immune response development (54)(55)(56)(57). Our results suggest that the list of their functions should also include regulation of cellular translation, at least during development of the antiviral response.…”

PET of Poly (ADP-Ribose) Polymerase Activity in Cancer: Preclinical Assessment and First In-Human Studies

“…Although the high normal pancreas activity may limit detection of the primary tumor, changes in pancreatic tumor uptake may still be helpful in determining treatment responses. In addition, PARP inhibitors also effectively treat hepatocellular carcinoma xenografts in mice (31), and human hepatocellular carcinoma has higher PARP expression than normal liver tissue (25) (25,28,29). The large proportion of parent compound remaining in the liver at 30 minutes was therefore most likely due to specific binding that prevented its metabolism.…”

Transcriptional Reprogramming and Resistance to Colonic Mucosal Injury in Poly(ADP-ribose) Polymerase 1 (PARP1)-deficient Mice

“…Poly-ADP-ribosylation itself is an evolutionarily highly conserved protein modification known to modulate chromatin structure, DNA metabolism, transcription factor activity, gene transcription, and overall cellular metabolism. Both extracellular and intracellular NAD ϩ -dependent enzymes have been shown to modulate immune processes (25,26). Two examples of extracellular ADP-ribosyltransferases (ARTS) ؊/؊ mice at baseline.…”