Compartmentation of NAD+-Dependent Signalling ⇑ ⇑ Friedrich Koch-Nolte A, , Stefan Fischer B, Friedrich Haag A, Mathias Ziegler B
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View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector FEBS Letters 585 (2011) 1651–1656 journal homepage: www.FEBSLetters.org Review Compartmentation of NAD+-dependent signalling ⇑ ⇑ Friedrich Koch-Nolte a, , Stefan Fischer b, Friedrich Haag a, Mathias Ziegler b, a Institute of Immunology, University Medical Center, Martinistr. 52, 20246 Hamburg, Germany b Department of Molecular Biology, University of Bergen, Thormøhlensgate 55, 5008 Bergen, Norway article info abstract Article history: NAD+ plays central roles in energy metabolism as redox carrier. Recent research has identified Received 25 February 2011 important signalling functions of NAD+ that involve its consumption. Although NAD+ is synthesized Revised 21 March 2011 mainly in the cytosol, nucleus and mitochondria, it has been detected also in vesicular and extracel- Accepted 21 March 2011 lular compartments. Three protein families that consume NAD+ in signalling reactions have been Available online 31 March 2011 characterized on a molecular level: ADP-ribosyltransferases (ARTs), Sirtuins (SIRTs), and NAD+ glyco- Edited by Sergio Papa, Gianfranco Gilardi hydrolases (NADases). Members of these families serve important regulatory functions in various and Wilhelm Just cellular compartments, e.g., by linking the cellular energy state to gene expression in the nucleus, by regulating nitrogen metabolism in mitochondria, and by sensing tissue damage in the extracel- + Keywords: lular compartment. Distinct NAD pools may be crucial for these processes. Here, we review the cur- + NAD+ rent knowledge about the compartmentation and biochemistry of NAD -converting enzymes that + ADP-ribosyltransferase control NAD signalling. Sirtuins Ó 2011 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved. NAD+ glycohydrolase NAD+ signalling 1. Introduction cuses on the biochemistry and compartmentation of NAD+-con- verting enzymes and of NAD+ itself in mammalian cells. The variety of physiological roles played by NAD+ has long been underestimated. Besides its vital functions as electron carrier, this 2. Conversions of NAD+ in signalling reactions pyridine nucleotide has important functions in signalling pathways [1–4]. The expression of several genes is linked to the redox state of In redox reactions, NAD+ is reversibly converted to NADH by + pyridine nucleotides via NAD /NADH-binding proteins that act as addition of two electrons and a proton to the nicotinamide ring, + redox sensors [5,6]. NAD also mediates post-translational protein thereby oxidizing metabolic intermediates (Fig. 1). In contrast, + modifications such as ADP-ribosylation and NAD -dependent pro- NAD+-dependent signalling reactions involve cleavage of the glyco- tein deacetylation [7–13]. Moreover, it is a direct precursor of mes- sidic bond between nicotinamide and ADP-ribose (wavy red line in senger molecules such as ADP-ribose (ADPR), cyclic ADP-ribose Fig. 1), i.e. the consumption of NAD+. These reactions result in the (cADPR) and O-acetyl-ADP-ribose (OAADPR), which are all in- transfer of the ADP-ribose moiety onto an acceptor, and release of 2+ + volved in intracellular Ca mobilization [14–16]. NAD -mediated the remaining nicotinamide. Therefore, these reactions are also re- signalling has now moved into focus as it governs fundamental ferred to as ADP-ribosyl transfer. biological processes both on a cellular and organismal level. To ful- fil such a broad range of functions a variety of mechanisms leading 2.1. NAD+-dependent protein modification and generation of second + to signalling conversions of NAD have evolved. Several enzymes messengers have been identified that catalyse different conversions of NAD+ leading to highly specific or rather general physiological conse- There are two principal types of NAD+-dependent signalling quences. This multitude of different signalling pathways requires reactions, the modification of proteins and the generation of mes- precise spatial organization. Several excellent recent reviews have senger molecules (Fig. 1). NAD+-dependent protein modifications covered various aspects of NAD signalling [1–16]. This review fo- include ADP-ribosylation reactions, that is, covalent attachment of ADP-ribose to specific amino acid residues, and the deacetyla- tion of lysine residues, catalysed by ADP-ribosyltransferases (ARTs) and sirtuins (SIRTs), respectively. ADP-ribosylation and deacetyla- ⇑ Corresponding authors. Fax: 4940 7410 54243 (F. Koch-Nolte). tion activate or inactivate target protein functions, as in the case of E-mail addresses: nolte@uke.de (F. Koch-Nolte), Mathias.Ziegler@mbi.uib.no (M. Ziegler). other posttranslational protein modifications. ADP-ribosylation is a 0014-5793/$36.00 Ó 2011 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.febslet.2011.03.045 1652 F. Koch-Nolte et al. / FEBS Letters 585 (2011) 1651–1656 Fig. 1. NAD+-converting enzymes and NAD+-dependent signalling. In redox reactions, NAD+ is reversibly converted to NADH by addition of two electrons and a proton to the nicotinamide ring. NAD+-converting enzymes cleave the glycosidic bond in NAD+ linking nicotinamide to ribose (indicated by the red wave). ADP-ribosyltransferases (ART) transfer ADPR onto amino acid residues (mono-ADP-ribosylation) or onto protein-linked ADP-ribose moieties (poly ADP-ribosylation). These protein modifications are reversed by ADP-ribosylhydrolases (ARH) and poly-ADP-ribosyl-glycohydrolase (PARG), liberating ADPR. Sirtuins (SIRT) catalyse NAD+-dependent deacetylation of proteins carrying acetylated lysine residues, yielding O-acetyl-ADPR (OAADPR). NAD-glycohydrolases (NADase) catalyse hydrolysis of NAD+ to ADPR and nicotinamide and cyclisation of ADPR to cyclic-ADPR. NADases also catalyse substitution of the nicotinamide moiety in NADP+ by nicotinic acid, yielding NAADP. These NAD+-derivatives can trigger elevation of intracellular Ca2+. reversible protein modification. Based on the extent of the modifi- linked ADP-ribose moieties, generating polymers of ADP-ribose cation, two modes can be distinguished, mono-ADP-ribosylation (PARsylation) [11]. One member of the ART family catalyses trans- and poly-ADP-ribosylation. ADP-ribose is released from mono- or fer of ADP-ribose to the terminal phosphate in t-RNA, initiating the poly-ADP-ribosylated proteins by ADP-ribosylhydrolases (ARHs) splicing reaction and the release of ADP-ribose 10–20 cyclic phos- and poly-ADP-ribose glycohydrolase (PARG) [10]. NAD+-dependent phate [22,23]. The ART fold has been found in proteins from all protein deacetylation involves transfer of the acetyl group from the kingdoms of life. In mammals, the ART family is the largest and, target protein onto ADP-ribose resulting in the formation of O- perhaps, most versatile of the three NAD+-converting protein fam- acetylated ADP-ribose [12]. Both ADPR and OAADPR have been ilies [10]. The 20–25 members of the ART family can be subdivided implicated as second messengers. Second messengers can also be into two structurally distinct subclasses designated ARTC and generated from NAD+ by ADP-ribosylcyclases/NAD+ glycohydrolas- ARTD on the basis of structural similarities to cholera and diphthe- es (NADases), yielding ADPR and cADPR [14]. NADases also cata- ria toxins, respectively [11]. Members of the smaller ARTC subfam- lyse the substitution of the nicotinamide moiety by nicotinic acid ily are expressed as GPI-anchored or secreted ecto-enzymes. in NADP (generated from NAD+ by NAD kinase), thereby forming Members of the larger ARTD subfamily include nuclear poly- nicotinic acid adenine dinucleotide phosphate (NAADP). All these ADP-ribosyltransferases, the t-RNA dephosophorylating enzyme NAD+-derived second messengers contribute to intracellular cal- TpT, and cytosolic oligo- and mono-ADP-ribosyltransferases. cium signalling by acting on calcium channels in the plasma mem- SIRTs have a low intrinsic NAD+ binding affinity, and NAD+- brane, endoplasmatic reticulum or lysosomes. binding to SIRTs generally requires prior binding of an acetylated peptide [18,19]. This peptide forms the central strand of a three- 2.2. Three NAD+-converting protein families stranded enzyme-substrate b-sheet in a crevice between the small Zn-binding domain and the large Rossman nucleotide-binding fold. In enzymes catalysing redox reactions the adenine and pyridine NAD+ binds in an extended conformation that exposes the alpha moieties of NAD+/NADH typically each are bound by a separate face of the nicotinamide ribose to the carbonyl oxygen of the acetyl classic Rossmann/Walker nucleotide-binding fold. The CtBP family lysine substrate promoting formation of an O-alkylamidate reac- of redox-responsive transcription factors similarly binds NAD+/ tion intermediate, the deacetylation of lysine and the release of NADH with two separate Rossman fold [17]. The enzymes catalys- O-acetyl ADP-ribose. The SIRT fold has been found in proteins from ing NAD+-consumption fall into three individual protein families all kingdoms of life [24,25]. The seven members of the mammalian containing distinct NAD+-binding domains. SIRTs use a single copy Sirtuin family are located in the nucleus, cytosol, and mitochondria of the Rossman fold for coordinating the adenine moiety of NAD+ [24]. [18,19]. ARTs and NADases carry rather distinct NAD+-binding NADases bind NAD+ in a bent conformation [26,27]. These en- domains. zymes facilitate base-exchange of the nicotinamide moiety,