Proteomic analyses identify ARH3 as a serine mono-ADP-ribosylhydrolase

Jeannette Abplanalp, Mario Leutert, Emilie Frugier, Kathrin Nowak, Roxane Feurer, Jiro Kato, Hans V. A. Kistemaker, Dmitri V. Filippov, Joel Moss, Amedeo Caflisch and Michael O. Hottiger ()
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Jeannette Abplanalp: University of Zurich
Mario Leutert: University of Zurich
Emilie Frugier: University of Zurich
Kathrin Nowak: University of Zurich
Roxane Feurer: University of Zurich
Jiro Kato: NIH
Hans V. A. Kistemaker: Leiden University
Dmitri V. Filippov: Leiden University
Joel Moss: NIH
Amedeo Caflisch: University of Zurich
Michael O. Hottiger: University of Zurich

Nature Communications, 2017, vol. 8, issue 1, 1-11

Abstract: Abstract ADP-ribosylation is a posttranslational modification that exists in monomeric and polymeric forms. Whereas the writers (e.g. ARTD1/PARP1) and erasers (e.g. PARG, ARH3) of poly-ADP-ribosylation (PARylation) are relatively well described, the enzymes involved in mono-ADP-ribosylation (MARylation) have been less well investigated. While erasers for the MARylation of glutamate/aspartate and arginine have been identified, the respective enzymes with specificity for serine were missing. Here we report that, in vitro, ARH3 specifically binds and demodifies proteins and peptides that are MARylated. Molecular modeling and site-directed mutagenesis of ARH3 revealed that numerous residues are critical for both the mono- and the poly-ADP-ribosylhydrolase activity of ARH3. Notably, a mass spectrometric approach showed that ARH3-deficient mouse embryonic fibroblasts are characterized by a specific increase in serine-ADP-ribosylation in vivo under untreated conditions as well as following hydrogen peroxide stress. Together, our results establish ARH3 as a serine mono-ADP-ribosylhydrolase and as an important regulator of the basal and stress-induced ADP-ribosylome.

Date: 2017
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DOI: 10.1038/s41467-017-02253-1

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