Targeting ADP-ribosylation as an antimicrobial strategy

Abstract

ADP-ribosylation (ADPr) is an ancient reversible modification of cellular macromolecules controlling major biological processes as diverse as DNA damage repair, transcriptional regulation, intracellular transport, immune and stress responses, cell survival and proliferation. Furthermore, enzymatic reactions of ADPr are central in the pathogenesis of many human diseases, including infectious conditions. By providing a review of ADPr signalling in bacterial systems, we highlight the relevance of this chemical modification in the pathogenesis of human diseases depending on host-pathogen interactions. The post-antibiotic era has raised the need to find alternative approaches to antibiotic administration, as major pathogens becoming resistant to antibiotics. An in-depth understanding of ADPr reactions provides the rationale for designing novel antimicrobial strategies for treatment of infectious diseases. In addition, the understanding of mechanisms of ADPr by bacterial virulence factors offers important hints to improve our knowledge on cellular processes regulated by eukaryotic homologous enzymes, which are often involved in the pathogenesis of human diseases.

Keywords: ADP-ribosyl transferase (ART); ADP-ribosylation; ART bacterial toxins; Antimicrobial strategies; Poly(ADP-ribose) polymerase (PARP).

Graphical abstract

Fig. 1

Schematic representation of the ADP-ribosylation reaction onto target protein. A) Mono-ADP-ribosylation reaction is catalysed by ADP-ribosyl transferases Diphteria toxin-like (ARTDs), ADP-ribosyl transferases Cholera toxin-like (ARTCs) and Sirtuins (SIRTs) in the presence of the NAD⁺. The modification, indicated as a single red ball, is reversed by selective ADP-ribose hydrolytic enzymes (MacroD1, MacroD2, TARG1, ARH1, ARH3) that show different amino acid-ADP-ribose linkage specificity, and by phosphodiesterases (NUDT16 and ENPP1). B) Poly(ADP-ribosyl)ation reaction is catalysed by ADP-ribosyl transferases Diphteria toxin-like (ARTDs). Linear or branched chains of Poly(ADP-ribose), indicated as red balls, are hydrolysed by selective ADP-ribose hydrolytic enzymes (PARG, ARH3, TARG1) and by phosphodiesterases (NUDT16 and ENPP1). Further details are reported in the text. NAM, nicotinamide; ARH1/ARH3, ADP-ribosyl acceptor hydrolases 1/3; NUDT16, nudix hydroxylase 16; PARG, Poly(ADP-ribosyl) glycohydrolase (endo-glyc, endo-glycolytic activity; exo-glyc, exo-glycolytic activity); TARG1, Terminal ADP-ribose glycosylhydrolase 1.

Fig. 2

Schematic representation of eukaryotic cellular mechanisms modulated by virulence factors displaying ADP-ribosylation activity.

Fig. 3

Schematic representation of Legionella pneumophila infection mediated by SdeA effector. By transferring a phosphoribosyl group on ER-resident substrates, such Reticulon-4 (RTN4) and several Rab proteins, SdeA induces the formation of ER-derived vesicles and their association with the Legionella-containing vacuoles (LCVs). LCVs also make contacts with ER and mitochondria, a phenomenon that affects physiological processes, such as ER-phagy and mitophagy.