Regulating Immunity via ADP-Ribosylation: Therapeutic Implications and Beyond

ADP-ribosylation serves as a checkpoint control for cell fate and actively drives a type of regulated cell death (parthanatos) to induce inflammation. ARTD1-mediated poly-ADP-ribosylation affects the mRNA stability of proinflammatory cytokines. The ARTD9–DTX3L complex acts as a potent antiviral mediator via chromatin modification and viral protein degradation. ARTD8 and ARTD9 regulate macrophage polarization via STAT1 phosphorylation and ADP-ribosylation. ARTD10-mediated mono-ADP-ribosylation of NEMO inhibits its degradation, consequently dampening NF-κB gene expression. Ectopic ARTC2.1 on microglia can regulate phagocytosis by modifying immunoglobulin receptors. Innate immune cells express pattern recognition receptors (PRRs) that recognize pathogen-associated molecular patterns (PAMPs) and endogenous danger-associated molecular patterns (DAMPs). Upon binding, PAMPs/DAMPs can initiate an immune response by activating lymphocytes, amplifying and modulating signaling cascades, and inducing appropriate effector responses. Protein ADP-ribosylation can regulate cell death, the release of DAMPs, as well as inflammatory cytokine expression. Inhibitors of ADP-ribosylation (i.e. PARP inhibitors) have been developed as therapeutic agents (in cancer), and are also able to dampen inflammation. We summarize here our most recent understanding of how ADP-ribosylation can regulate the different phases of an immune response. Moreover, we examine the potential clinical translation of pharmacological ADP-ribosylation inhibitors as putative treatment strategies for various inflammation-associated diseases (e.g. sepsis, chronic inflammatory diseases, and reperfusion injury). Innate immune cells express pattern recognition receptors (PRRs) that recognize pathogen-associated molecular patterns (PAMPs) and endogenous danger-associated molecular patterns (DAMPs). Upon binding, PAMPs/DAMPs can initiate an immune response by activating lymphocytes, amplifying and modulating signaling cascades, and inducing appropriate effector responses. Protein ADP-ribosylation can regulate cell death, the release of DAMPs, as well as inflammatory cytokine expression. Inhibitors of ADP-ribosylation (i.e. PARP inhibitors) have been developed as therapeutic agents (in cancer), and are also able to dampen inflammation. We summarize here our most recent understanding of how ADP-ribosylation can regulate the different phases of an immune response. Moreover, we examine the potential clinical translation of pharmacological ADP-ribosylation inhibitors as putative treatment strategies for various inflammation-associated diseases (e.g. sepsis, chronic inflammatory diseases, and reperfusion injury). a class of enzymes in bacteria, viruses, and all mammalian cells but not yeast. They catalyze the post-translational modification, ADP-ribosylation. DAMPs that are structural components of the host (e.g., HMGB1); these are passively released from necrotic cells but can also be actively secreted by immune cells in response to pathogen encounter. Their release triggers an immune response to clear cellular debris and remodel the affected tissue or to clear pathogens. a high-affinity PAR-binding protein localizing to the mitochondrial intermembrane space where it plays essential roles in the mitochondrial respiratory chain. A smaller pool of AIF associates with the outer mitochondrial membrane. Its release is crucial for different modes of programmed cell death. summarizes different processes allowing the ordered degradation and recycling of cellular components; an important survival mechanism in response to stress (including genotoxic stress, nutrient starvation, and hypoxia). see Writers the association of nucleic acids (DNA/RNA) and proteins (mostly histones) that organize genetic information. cell-derived molecules that can initiate and perpetuate immunity in response to trauma, ischemia, cancer, and other settings of tissue damage in the absence or presence of overt pathogenic infection (e.g. alarmins). ADP-ribosylation is reversed by hydrolysis of the poly(ADP-ribose) (PAR) chain and removal of the protein-bound mono(ADP-ribose) (MAR) by different enzymes ('erasers') such as poly(ADP-ribose) glycohydrolase (PARG). caused by exposure to UV light, radiation, or chemical agents that induce mutations in DNA. The DNA repair machinery resolves these lesions that can eventually give rise to transformed cells and cancer. macrophages exhibit a wide range of effector functions that depend on polarization by different cytokines. The most prominent macrophage types have been arbitrarily categorized as proinflammatory M1-like (IFN-γ-producing) and anti-inflammatory/regulatory M2-like (IL-4-producing). some ARTs attach a single ADP-ribose moiety to target proteins (MARylation). Other ARTs can extend the initial modification to PARylation leading to linear or branched chains. excessive, predominantly ARTD1-mediated PARylation in response to genotoxic stress or other signaling events can deplete (exhaust) the nuclear NAD+ pool. This dramatically compromises the energy state of a cell. a coenzyme which transfers two electrons during its oxidation from NADH to NAD+. It plays an important role in cellular energy metabolism and serves as the substrate for ADP-ribosylation. triggering of TLRs induces the canonical NF-κB inflammatory signaling cascade with phosphorylation of IκB and its subsequent ubiquitination and degradation. In turn, released p50/p65 translocates into the nucleus to initiate gene expression. a caspase-independent mode of cell death which combines apoptotic and necrotic features (par for PAR polymer, and Thanatos is the personification of death in Greek mythology). It is induced by the release of complex PAR chains from the nucleus, resulting in mitochondrial depolarization and AIF release. these initiate and perpetuate the infectious pathogen-induced inflammatory response; PAMPs include structural components of foreign bacteria (e.g., lipopolysaccharide, LPS), viruses, or parasites that are recognized by conserved host receptors that identify foreign elements and license the initiation of an immune response to clear the infection. also known as ARTDs; see Writers. a transmembrane pattern recognition receptor; detects specific glycoproteins through a common structural motif, inducing proinflammatory signaling (e.g., HMGB1, an agonistic ligand of RAGE). the occurrence of the hallmarks of inflammation (heat, redness, swelling, pain, and loss of function) in the absence of a pathogen. Prominent examples include the inhalation of sterile irritants, ischemia–reperfusion injury, gout, Alzheimer's disease, and cancer. a genetic interaction in which single-gene defects are compatible with cell viability, but the combination ('synthesis') of gene defects results in cell death. BRCA mutated cells are up to 1000-fold more sensitive to PARPi than are wild-type cells. a family of membrane-bound receptors of the innate immune system that are typically expressed by macrophages and dendritic cells. They recognize a specific set of evolutionary conserved foreign structures to rapidly induce an immune response. intracellular ADP-ribosylation is mediated by diphtheria toxin-like ADP-ribosyltransferases (ARTDs, also known as PARPs), which catalyze both the initial MARylation and the subsequent elongation and branching (PARylation). While some of the ARTD family members exhibit all of these activities, most of them are pure mono-ADP-ribosyltransferases or do not catalyze branching. Extracellular ADP-ribosylation is catalyzed by the ectopic cholera toxin-like ARTs (ARTCs) that catalyze MARylation.