ARH1 in Health and Disease.

Arginine-specific mono-adenosine diphosphate (ADP)-ribosylation is a nicotinamide adenine dinucleotide (NAD)-dependent, reversible post-translational modification involving the transfer of an ADP-ribose from NAD by bacterial toxins and eukaryotic ADP-ribosyltransferases (ARTs) to arginine on an acceptor protein or peptide. ADP-ribosylarginine hydrolase 1 (ARH1) catalyzes the cleavage of the ADP-ribose-arginine bond, regenerating (arginine)protein. Arginine-specific mono-ADP-ribosylation catalyzed by bacterial toxins was first identified as a mechanism of disease pathogenesis.

The ARH and Macrodomain Families of α-ADP-ribose-acceptor Hydrolases Catalyze α-NAD Hydrolysis.

ADP-ribosyltransferases transfer ADP-ribose from β-NAD to acceptors; ADP-ribosylated acceptors are cleaved by ADP-ribosyl-acceptor hydrolases (ARHs) and proteins containing ADP-ribose-binding modules termed macrodomains. On the basis of the ADP-ribosyl-arginine hydrolase 1 (ARH1) stereospecific hydrolysis of α-ADP-ribosyl-arginine and the hypothesis that α-NAD is generated as a side product of β-NAD/ NADH metabolism, we proposed that α-NAD was a substrate of ARHs and macrodomain proteins. Here, we report that ARH1, ARH3, and macrodomain proteins (i.

Role of a TRIM72 ADP-ribosylation cycle in myocardial injury and membrane repair.

Mono-ADP-ribosylation of an (arginine) protein catalyzed by ADP-ribosyltransferase 1 (ART1) - i.e., transfer of ADP-ribose from NAD to arginine - is reversed by ADP-ribosylarginine hydrolase 1 (ARH1) cleavage of the ADP-ribose-arginine bond.

Mono-ADP-Ribosylation Catalyzed by Arginine-Specific ADP-Ribosyltransferases.

Methods are described for determination of arginine-specific mono-ADP-ribosyltransferase activity of purified proteins and intact cells by monitoring the transfer of ADP-ribose from NAD to a model substrate, e.g., arginine, agmatine, and peptide (human neutrophil peptide-1 [HNP1]), and for the nonenzymatic hydrolysis of ADP-ribose-arginine to ornithine, a noncoded amino acid.

Nonenzymatic conversion of ADP-ribosylated arginines to ornithine alters the biological activities of human neutrophil peptide-1.

Activated neutrophils, recruited to the airway of diseased lung, release human neutrophil peptides (HNP1-4) that are cytotoxic to airway cells as well as microbes. Airway epithelial cells express arginine-specific ADP ribosyltransferase (ART)-1, a GPI-anchored ART that transfers ADP-ribose from NAD to arginines 14 and 24 of HNP-1. We previously reported that ADP-ribosyl-arginine is converted nonenzymatically to ornithine and that ADP-ribosylated HNP-1 and ADP-ribosyl-HNP-(ornithine) were isolated from bronchoalveolar lavage fluid of a patient with idiopathic pulmonary fibrosis, indicating that these reactions occur in vivo.

Evidence for a common mechanism of SIRT1 regulation by allosteric activators.

A molecule that treats multiple age-related diseases would have a major impact on global health and economics. The SIRT1 deacetylase has drawn attention in this regard as a target for drug design. Yet controversy exists around the mechanism of sirtuin-activating compounds (STACs).

ADP-ribosylation of human defensin HNP-1 results in the replacement of the modified arginine with the noncoded amino acid ornithine.

Defensins (e.g., human neutrophil peptides, or HNPs) contribute to innate immunity through diverse actions, including microbial killing; high concentrations are present in the lung in response to inflammation.

TSC2 loss in lymphangioleiomyomatosis cells correlated with expression of CD44v6, a molecular determinant of metastasis.

Lymphangioleiomyomatosis (LAM), a rare multisystem disease found primarily in women of childbearing age, is characterized by the proliferation of abnormal smooth muscle-like cells, LAM cells, that form nodules in the pulmonary interstitium. Proliferation of LAM cells results, in part, from dysfunction in tuberous sclerosis complex (TSC) genes TSC1 (hamartin) and/or TSC2 (tuberin). Identification of LAM cells in donor lungs, their isolation from blood, and their presence in urine, chylous ascites, and pleural effusions are consistent with their ability to metastasize.

ART2, a T cell surface mono-ADP-ribosyltransferase, generates extracellular poly(ADP-ribose).

NAD functions in multiple aspects of cellular metabolism and signaling through enzymes that covalently transfer ADP-ribose from NAD to acceptor proteins, thereby altering their function. NAD is a substrate for two enzyme families, mono-ADP-ribosyltransferases (mARTs) and poly(ADP-ribose) polymerases (PARPs), that covalently transfer an ADP-ribose monomer or polymer, respectively, to acceptor proteins. ART2, a mART, is a phenotypic marker of immunoregulatory cells found on the surface of T lymphocytes, including intestinal intraepithelial lymphocytes (IELs).

ADP-ribosyltransferase-specific modification of human neutrophil peptide-1.

Epithelial cells lining human airways and cells recruited to airways participate in the innate immune response in part by releasing human neutrophil peptides (HNP). Arginine-specific ADP-ribosyltransferases (ART) on the surface of these cells can catalyze the transfer of ADP-ribose from NAD to proteins. We reported that ART1, a mammalian ADP-ribosyltransferase, present in epithelial cells lining the human airway, modified HNP-1, altering its function.

Regulatory role of arginine 204 in the catalytic activity of rat alloantigens ART2a and ART2b.

ART2a (RT6.1) and ART2b (RT6.2) are NAD glycohydrolases (NADases) that are linked to T lymphocytes by glycosylphosphatidylinositol anchors.

ADP ribosylation of human neutrophil peptide-1 regulates its biological properties.

In human airways, epithelial cells lining the lumen and intraluminal cells (e.g., polymorphonuclear cells) participate in the innate immune response.

Giles F. Filley Lecture. Genetics and gene expression in lymphangioleiomyomatosis.

Lymphangioleiomyomatosis (LAM) is a disease of unknown etiology that is characterized by the proliferation of abnormal smooth muscle cells (LAM cells) in the lung, which leads to cystic parenchymal destruction and progressive respiratory failure. Recent evidence suggests that the proliferative and invasive nature of LAM cells may be due, in part, to somatic mutations in the TSC2 gene, which has been implicated in the pathogenesis of tuberous sclerosis complex. Here, we describe the clinical and molecular characteristics of LAM, as well as the efforts now under way to understand the genetic and biochemical factors that lead to progressive pulmonary destruction and, ultimately, to lung transplantation or death.