A novel predicted ADP-ribosyltransferase family conserved in eukaryotic evolution

Abstract

The presence of many completely uncharacterized proteins, even in well-studied organisms such as humans, seriously hampers full understanding of the functioning of the living cells. ADP-ribosylation is a common post-translational modification of proteins; also nucleic acids and small molecules can be modified by the covalent attachment of ADP-ribose. This modification, important in cellular signalling and infection processes, is usually executed by enzymes from the large superfamily of ADP-ribosyltransferases (ARTs)Here, using bioinformatics approaches, we identify a novel putative ADP-ribosyltransferase family, conserved in eukaryotic evolution, with a divergent active site. The hallmark of these proteins is the ART domain nestled between flanking leucine-rich repeat (LRR) domains. LRRs are involved in innate immune surveillance.The novel family appears as likely novel ADP-ribosylation “writers”, previously unnoticed new players in cell signaling by this emerging post-translational modification. We propose that this family, including its human member LRRC9, may be involved in an ancient defense mechanism, with analogies to the innate immune system, and coupling pathogen detection to ADP-ribosyltransfer signalling.

Uncovering the Invisible: Mono-ADP-ribosylation Moved into the Spotlight

“…To date, besides ARTD1, SIRT4, ARH3, PARG and MacroD1 are also proposed to be involved in the regulation of ADP-ribosylation in mitochondria by catalyzing either its synthesis or removal [ 28 , 29 , 187 , 188 , 189 , 190 , 191 , 192 , 193 ]. In addition to the potential contribution of those four enzymes (reviewed in detail elsewhere [ 39 ]), a recent study proposed NEURL4 as a new ADP-ribosylation catalyzing enzyme within mitochondria [ 16 , 17 ].…”

“…In addition to these enzymes, recent studies have proposed that other protein families, including NEURL4-like enzymes and certain leucine-rich repeat-containing enzymes, are able to catalyze ADP-ribosylation as well [16,17]. In recent years, protein ADP-ribosylation has emerged as a complex and dynamic post-translational modification that either directly affects the modified proteins or leads to modification-dependent protein complex formation thus serving as a signaling molecule [18].…”