ADP‐ribosylation in evasion, promotion and exacerbation of immune responses

Abstract

ADP‐ribosylation is the addition of one or more (up to some hundreds) ADP‐ribose moieties to acceptor proteins. This evolutionary ancient post‐translational modification (PTM) is involved in fundamental processes including DNA repair, inflammation, cell death, differentiation and proliferation, among others. ADP‐ribosylation is catalysed by two major families of enzymes: the cholera toxin‐like ADP‐ribosyltransferases (ARTCs) and the diphtheria toxin‐like ADP‐ribosyltransferases (ARTDs, also known as PARPs). ARTCs sense and use extracellular NAD, which may represent a danger signal, whereas ARTDs are present in the cell nucleus and/or cytoplasm. ARTCs mono‐ADP‐ribosylate their substrates, whereas ARTDs, according to the specific family member, are able to mono‐ or poly‐ADP‐ribosylate target proteins or are devoid of enzymatic activity. Both mono‐ and poly‐ADP‐ribosylation are dynamic processes, as specific hydrolases are able to remove single or polymeric ADP moieties. This dynamic equilibrium between addition and degradation provides plasticity for fast adaptation, a feature being particularly relevant to immune cell functions. ADP‐ribosylation regulates differentiation and functions of myeloid, T and B cells. It also regulates the expression of cytokines and chemokines, production of antibodies, isotype switch and the expression of several immune mediators. Alterations in these processes involve ADP‐ribosylation in virtually any acute and chronic inflammatory/immune‐mediated disease. Besides, pathogens developed mechanisms to contrast the action of ADP‐ribosylating enzymes by using their own hydrolases and/or to exploit this PTM to sustain their virulence. In the present review, we summarize and discuss recent findings on the role of ADP‐ribosylation in immunobiology, immune evasion/subversion by pathogens and immune‐mediated diseases.

ADP‐ribosyltransferases, an update on function and nomenclature

“…The majority of mammalian proteins that belong to clade 1 are referred to as PARPs and tankyrases (TNKS) or together as ARTDs (see below for definitions), which are located intracellularly [1,4,7,8,21]. The proteins expressed in mammals belonging to clade 2 are Accepted Article extracellular or secreted and designated ARTCs or ecto-ARTs [22][23][24][25]. The proposition to use the terminology ARTD and ARTC for two structurally related but distinct families of ARTs was made more than ten years ago [20].…”

“…They regulate multiple activities including immune functions, signaling, and ER stress response ( Fig. 3 ) [ 22 , 23 ]. Of note is that ARTC enzymes modify primarily arginines.…”

Intracellular mono-ADP-ribosyltransferases at the host–virus interphase

“…Discussing these findings in detail is beyond the scope of this review. We refer the reader to excellent, recent reviews that summarize and discuss these functions [ 15 – 17 ].…”

Structural aspects of chemical modifications in the MHC-restricted immunopeptidome; Implications for immune recognition

“…PTMs including phosphorylation, methylation, acetylation and deamidation impact also on cellular DNA sensor functions using diverse mechanisms, such as direct regulation of enzymatic activity, protein-protein and protein-DNA interactions, protein translocations and protein turnover ( Song et al, 2021 ). ADP-ribosylation, which is the addition of one up to 200 ADP-ribose moieties from NAD to Ser, Glu, Asp or Arg residues on intra- or extracellular target proteins regulates T and B cell function and differentiation capacities ( Rosado and Pioli 2021 ). Several bacterial toxins represent significant virulence through their ADP-ribosylation capacity.…”