Structure and function of the ARH family of ADP-ribosyl-acceptor hydrolases

Abstract

ADP-ribosylation is a post-translational protein modification, in which ADP-ribose is transferred from nicotinamide adenine dinucleotide (NAD+) to specific acceptors, thereby altering their activities. The ADP-ribose transfer reactions are divided into mono- and poly-(ADP-ribosyl)ation. Cellular ADP-ribosylation levels are tightly regulated by enzymes that transfer ADP-ribose to acceptor proteins (e.g. ADP-ribosyltransferases, poly-(ADP-ribose) polymerases (PARP)) and those that cleave the linkage between ADP-ribose and acceptor (e.g. ADP-ribosyl-acceptor hydrolases (ARH), poly-(ADP-ribose) glycohydrolases (PARG)), thereby constituting an ADP-ribosylation cycle. This review summarizes current findings related to the ARH family of proteins. This family comprises three members (ARH1-3) with similar size (39 kDa) and amino acid sequence. ARH1 catalyzes the hydrolysis of the N-glycosidic bond of mono-(ADP-ribosyl)ated arginine. ARH3 hydrolyzes poly-(ADP-ribose) (PAR) and O-acetyl-ADP-ribose. The different substrate specificities of ARH1 and ARH3 contribute to their unique roles in the cell. Based on a phenotype analysis of ARH1−/− and ARH3−/− mice, ARH1 is involved in the action by bacterial toxins as well as in tumorigenesis. ARH3 participates in the degradation of PAR that is synthesized by PARP1 in response to oxidative stress-induced DNA damage; this hydrolytic reaction suppresses PAR-mediated cell death, a pathway termed parthanatos.

Functional Role of ADP-Ribosyl-Acceptor Hydrolase 3 in poly(ADPRibose) Polymerase-1 Response to Oxidative Stress

“…Using ARH3 −/− MEFs, we have elucidated two cellular functions involving the PAR hydrolytic activity of ARH3 [1, 14–16]. Through its PAR-degrading activity, ARH3 regulates PAR metabolism in the nucleus, cytoplasm, and mitochondria.…”

“…The ADP-ribosyl-acceptor hydrolase (ARH) family is composed of three 39-kDa proteins, ARH1-3 [1]. ARH1, the founding member of the ARH family, was initially isolated from turkey erythrocytes in 1988, and subsequently from human, rat, and mouse tissues [2, 3].…”

“…Using ARH1 −/− mice and cells, we have found that ARH1 has crucial roles in tumorigenesis and in counteracting intoxication by cholera toxin [6, 7]. Detailed biological properties and cellular functions of ARH1 have been reviewed [1, 8]. …”

Molecular Imaging of Sirtuin1 Expression–Activity in Rat Brain Using Positron-Emission Tomography–Magnetic-Resonance Imaging with [18F]-2-Fluorobenzoylaminohexanoicanilide

“…Also, it is conceivable that the transient nature of 2-[ 18 F]BzAHA-derived-radioactivity retention in the cells is due to the cleavage or removal of the 2-[ 18 F]benzoyl group from the ADN, similar to the previously reported cleavage of acetyl moieties from an ADN groups by esterases such as ARH3. 34,35 …”

Post-translational modifications in mitochondria: protein signaling in the powerhouse

“…Mechanisms of PARP inhibition include auto-PARylation, phosphorylation by protein kinase C, and sumoylation [131–133]. PARylation in the cell is controlled by the enzymes Poly (ADP-Ribose) glycohydrolase (PARG) and ADP-ribosyl protein hydrolase-3 (ARH-3), which rapidly degrade PAR [134, 135]. …”