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Exploring NAD+ Metabolism in Host–Pathogen Interactions

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Exploring NAD+ Metabolism in Host–Pathogen Interactions View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Universidade do Minho: RepositoriUM Cell. Mol. Life Sci. DOI 10.1007/s00018-015-2119-4 Cellular and Molecular Life Sciences REVIEW Exploring NAD+ metabolism in host–pathogen interactions 1,2 1,2 1,2 Ineˆs Mesquita • Patrı´cia Varela • Ana Belinha • 1,2 4 3 Joana Gaifem • Mireille Laforge • Baptiste Vergnes • 4,5 1,2 Je´roˆme Estaquier • Ricardo Silvestre Received: 9 July 2015 / Revised: 27 November 2015 / Accepted: 14 December 2015 Ó Springer International Publishing 2015 Abstract Nicotinamide adenine dinucleotide (NAD?)is NAD? metabolism during host–pathogen interactions a vital molecule found in all living cells. NAD? intracel- emphasizing its potential for treatment of infectious lular levels are dictated by its synthesis, using the de novo diseases. and/or salvage pathway, and through its catabolic use as co-enzyme or co-substrate. The regulation of NAD? Keywords Nicotinamide adenine dinucleotide (NAD?) Á metabolism has proven to be an adequate drug target for Host-pathogen interaction Á NAD?/NADH ratio Á several diseases, including cancer, neurodegenerative or NADPH Á Sirtuins Á L-tryptophan inflammatory diseases. Increasing interest has been given ? to NAD metabolism during innate and adaptive immune Nicotinamide adenine dinucleotide (NAD?) was initially responses suggesting that its modulation could also be discovered by Sir Arthur Harden as a ‘cozymase’ for yeast relevant during host–pathogen interactions. While the ? fermentation over 100 years ago. The succeeding work con- maintenance of NAD homeostatic levels assures an ade- tributed to the identification of NAD? as a player in hundreds quate environment for host cell survival and proliferation, ? of biochemical reactions through its role in redox reactions. fluctuations in NAD or biosynthetic precursors bioavail- NAD? is either consumed as a co-substrate by NAD?-con- ability have been described during host–pathogen suming enzymes or used as an electron carrier in redox interactions, which will interfere with pathogen persistence reactions. Yet, the intracellular NAD?/NADH ratio is key to or clearance. Here, we review the double-edged sword of the maintenance of an adequate metabolic status and cell survival. Growing evidences indicate that NAD? biosynthetic pathways and metabolism are playing a major role in host– & Je´roˆme Estaquier pathogen interactions. In this review, we overview these [email protected] mechanisms highlighting the role of NAD? metabolism as an & Ricardo Silvestre attractive therapeutic target for microbe infections. [email protected] 1 Microbiology and Infection Research Domain, Life and Health Sciences Research Institute (ICVS), School of Health 1 Sciences, University of Minho, Braga, Portugal NAD biosynthesis: where the tale begins 2 ICVS/3B’s-PT Government Associate Laboratory, NAD1 biosynthesis in mammalian cells Braga/Guimara˜es, Portugal 3 ´ MIVEGEC (IRD 224-CNRS 5290-Universite Montpellier), The biosynthesis of NAD? in mammals occurs through Institut de Recherche pour le De´veloppement (IRD), Montpellier, France two different pathways: the de novo and the salvage pathways (Fig. 1). The de novo pathway begins with the 4 CNRS FR 3636, Universite´ Paris Descartes, 75006 Paris, France uptake and conversion of dietary L-tryptophan in N-for- mylkynurenine, which is mediated by the rate-limiting 5 Centre de Recherche du CHU de Que´bec, Universite´ Laval, Quebec G1V 4G2, Canada indoleamine 2,3-dioxygenase (IDO) or tryptophan 2,3- 123 I. Mesquita et al. Fig. 1 NAD? biosynthetic pathways and redox metabolism of acid mononucleotide, NAMPT nicotinamide phosphoribosyltrans- mammals. The de novo pathway for NAD? biosynthesis is indicated ferase, NAPT nicotinic acid phosphoribosyltransferase, NMNAT in green, the salvage pathway is indicated in orange and the redox nicotinamide mononucleotide adenylyltransferase, NMN nicoti- metabolism of NAD/NADP is indicated in blue. IDO indoleamine namide mononucleotide, NR nicotinamide riboside, NRK 2,3-dioxygenase, NAD? nicotinamide adenine dinucleotide, NaAD nicotinamide riboside kinase, TDO tryptophan 2,3-dioxygenase, Trp nicotinic acid dinucleotide, NADP nicotinamide adenine dinucleotide tryptophan phosphate, NADK NAD? kinase, NAM nicotinamide; NaMN nicotinic dioxygenase (TDO). After several subsequent enzymatic of NAD?/NADH ratio. Eukaryotic cells maintain an reactions, quinolinic acid is formed and further condensed independent mitochondrial and cytosolic NAD? pool, in nicotinic acid mononucleotide (NaMN). NaMN is con- which allows coping with distinct stimuli and challenges verted in nicotinic acid adenine dinucleotide (NaAD) by [103]. NAD? pools are used for protein post-translational the activity of nicotinamide mononucleotide adenylyl- modifications, such as protein mono- or poly(ADP ribo- transferase isoforms (NMNATs 1–3). The completion of syl)ation or deacetylation, or for the production of second the de novo pathway occurs with the production of NAD? messengers, such as the Ca2?-mobilizing compounds by the glutamine-dependent NAD? synthase [50]. cyclic adenosine diphosphoribose (cADPR) and nicotinic NAD? levels can also be restored through the import or acid adenine dinucleotide phosphate (NAADP). Nonethe- recycling of nicotinic acid (NA), nicotinamide (NAM) or less, the contribution of NAD? fluxes between nicotinamide riboside (NR) in the salvage pathway. NA is compartments and its consequent homeostasis is yet to be converted to NaMN by the NA phosphoribosyltransferase completely understood. (NAPT) to generate NAD? through the Preiss–Handler As different processes require different intermediates pathway converging with the de novo pathway. NAM is used and, therefore different NAD? levels, it has become clearer asasourceofNAD? through the activity of NAM phospho- that this molecule is stored in a compartment-specific ribosyltransferase (NAMPT), which is the rate-limiting fashion. Cytosol and mitochondria represent the main enzyme of the salvage pathway [77]. In addition, nicotinamide intracellular NAD? pools [19]. The NAD?/NADH ratio is ribose kinase (NRK) induces the phosphorylation of NR in about 100-fold lower in mitochondria when compared with NAM mononucleotide (NMN), which is the converging point the cytosolic compartment. Indeed, it has been estimated of the salvage pathway culminating in the production of that the cytosolic compartment display NAD?/NADH NAD? through the adenylation of NMN by NMNAT. Finally, ratios ranging between 60 and 700 whilst mitochondrial are NAD? is further phosphorylated to NADP? by the cytosolic set at 7 to 8 [100]. This ratio reflects the overall redox state NAD kinase (NADk) to enter redox metabolism. of the cell and its maintenance is crucial for cell survival through the control of energy metabolism. The defined NAD1 pools: a dynamic regulation for achieving compartmentalization allows a preservation of oxidative ideal distribution phosphorylation in the event of a massive cytosolic NAD? depletion with maintenance of cell viability and ATP stores Metabolic functions and the modulation of several bio- for a short period of time. The ‘‘Mitochondrial Oasis logical processes are dependent on the cellular homeostasis Effect’’ refers to the capacity of mitochondria to dictate 123 Exploring NAD? metabolism in host–pathogen interactions cell survival through maintenance of specific NAD? pools, established that NMN and NR are the biochemical sources even after depletion of nuclear and cytosolic ones. This for NAD? in H. influenzae. Two proteins were identified to protection was shown to be dependent on NAMPT activity play a key role in the uptake of NAD?; the outer membrane via mitochondrial SIRT3 and SIRT4 [103]. lipoprotein e(P4) and a periplasmic NAD nucleotidase The compartmentalization of NAD? synthesis is (NadN). The e(P4) outer membrane protein and the NadN achieved by tightly controlled localization of the three periplasmic enzyme convert NAD? to NMN and NR [38]. NMNAT isoforms; nuclear NMNAT1, cytosolic NMNAT2 The latter is able to cross the inner membrane to the cyto- and mitochondrial NMNAT3 [58]. The rigorous subcellu- plasm, where NadR recycles it back to NAD? by lar localization of mammalian NMNAT isoforms suggests phosphorylating NR to NMN that is further adenylated to a predominant role for this enzyme in determining the NAD? [44, 87]. Shigella spp., the pathological agent of subcellular NAD? pool distribution. NMNAT1 is the most bacillary dysentery, lacks a de novo pathway for the syn- efficient enzyme involved in the forward and reverse thesis of NAD? and therefore requires nicotinic acid for equilibrium reaction that originates adenylyltransference or growth [51]. As most prokaryotes, Shigella converts L-as- pyrophosphorylysis, respectively. Although NMNAT1 partate into the precursor for NAD? synthesis quinolinic acid utilizes nicotinamide mononucleotide (NMN) as a major depending on the enzyme complex composed by quinolate ? precursor for NAD synthesis, it was shown that synthase (NadA) and L-aspartate oxidase (NadB). Quinolinic NMNAT2 displays a high affinity for nicotinic acid acid is subsequently converted into nicotinic acid mononu- mononucleotide (NaMN) that originates nicotinic acid cleotide by quinolinate quinolinic acid concentration adenine dinucleotide (NAAD), whilst hNMNAT3 was decreases the intracellular spreading of Shigella, which demonstrated to be the isoform with lower selectivity for confirmed the occurrence of a selective pressure
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