title: Beyond DNA repair, the immunological role of PARP-1 and its siblings.
abstract: ADP-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.
authors.affiliation: Laboratory of B cell development, Ospedale Pediatrico Bambino Gesù IRCCS, Rome, Italy.
authors.forename: Maria Manuela
authors.initials: MM
authors.lastname: Rosado
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Bennici
authors.forename: Flavia
authors.initials: F
authors.lastname: Novelli
authors.forename: Claudio
authors.initials: C
authors.lastname: Pioli
mesh_terms: D000818:Animals; D016923:Cell Death; D002454:Cell Differentiation; D004260:DNA Repair; D006801:Humans; D007113:Immunity, Innate; D007249:Inflammation / Q000201:enzymology / Q000276:immunology; D008213:Lymphocyte Activation; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000276:immunology* / Q000378:metabolism; D013601:T-Lymphocytes / Q000201:enzymology / Q000276:immunology
chemical_list: C499320:PARP1 protein, human; C499321:Parp1 protein, mouse; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases
keywords: autoimmunity; immunotherapeutics; inflammation