A nicotinamide phosphoribosyltransferase–GAPDH interaction sustains the stress-induced NMN/NAD+ salvage pathway in the nucleus

Grolla, Ambra A.; Miggiano, Riccardo; Marino, Daniele Di; Bianchi, Michele M.; Gori, Alessandro; Orsomando, Giuseppe; Gaudino, Federica; Galli, Ubaldina; Grosso, Erika Del; Mazzola, Francesca; Angeletti, Carlo Alberto; Guarneri, Martina; Torretta, Simone; Calabrò, Marta; Boumya, Sara; Fan, Xiaorui; Colombo, Giorgia; Travelli, Cristina; Rocchio, Francesca; Aronica, Eleonora; Wohlschlegel, James A.; Deaglio, Silvia; Rizzi, Menico; Genazzani, Armando A.; Garavaglia, Silvia

doi:10.1074/jbc.ra119.010571

Cited by 22 publications

(11 citation statements)

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“…Moreover, NAMPT cytosol/nucleus localization changes according to cell cycle phases: it is excluded from the nucleus immediately after mitosis and it migrates back into it as the cell cycle progresses (111). These data were confirmed also by Grolla et al that demonstrated a transport of NAMPT into the nucleus, GAPDH-mediated, in response to DNA damage (112). On the contrary, the presence of NAMPT in mitochondria remains controversial (30,46,109).…”

Section: Namptmentioning

confidence: 66%

NAMPT and NAPRT: Two Metabolic Enzymes With Key Roles in Inflammation

2020

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Nicotinamide phosphoribosyltransferase (NAMPT) and nicotinate phosphoribosyltransferase (NAPRT) are two intracellular enzymes that catalyze the first step in the biosynthesis of NAD from nicotinamide and nicotinic acid, respectively. By fine tuning intracellular NAD levels, they are involved in the regulation/reprogramming of cellular metabolism and in the control of the activity of NAD-dependent enzymes, including sirtuins, PARPs, and NADases. However, during evolution they both acquired novel functions as extracellular endogenous mediators of inflammation. It is well-known that cellular stress and/or damage induce release in the extracellular milieu of endogenous molecules, called alarmins or damage-associated molecular patterns (DAMPs), which modulate immune functions through binding pattern recognition receptors (PRRs), such as Toll-like receptors (TLRs), and activate inflammatory responses. Increasing evidence suggests that extracellular (e)NAMPT and eNAPRT are novel soluble factors with cytokine/adipokine/DAMP-like actions. Elevated eNAMPT were reported in several metabolic and inflammatory disorders, including obesity, diabetes, and cancer, while eNAPRT is emerging as a biomarker of sepsis and septic shock. This review will discuss available data concerning the dual role of this unique family of enzymes.

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Section: Namptmentioning

confidence: 66%

NAMPT and NAPRT: Two Metabolic Enzymes With Key Roles in Inflammation

2020

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“…Indeed, it is now emerging that it is much more than a simple workhorse to replenish NAD. The complexity of this enzyme is exemplified by the fact that, while the role as an extracellular cytokine is yet not fully elucidated, it has just emerged that it can also shuttle to the nucleus in cells to provide NMN/NAD on site (Svoboda et al, 2019;Grolla et al, 2020). Although more information has to be gathered, it is now apparent that the hypothesis of using NAMPT inhibitors as a single agent is possibly flawed by the occurrence of side effects.…”

Section: Resultsmentioning

confidence: 99%

Recent Advances in NAMPT Inhibitors: A Novel Immunotherapic Strategy

et al. 2020

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Nicotinamide adenine dinucleotide (NAD) is a cofactor of many enzymatic reactions as well as being a substrate for a number of NAD-consuming enzymes (e.g., PARPS, sirtuins, etc). NAD can be synthesized de novo starting from tryptophan, nicotinamide, nicotinic acid, or nicotinamide riboside from the diet. On the other hand, the nicotinamide that is liberated by NAD-consuming enzymes can be salvaged to reform NAD. In this former instance, nicotinamide phosphoribosyltransferase (NAMPT) is the bottleneck enzyme. In the many cells in which the salvage pathway is predominant, NAMPT, therefore, represents an important controller of intracellular NAD concentrations, and as a consequence of energy metabolism. It is, therefore, not surprising that NAMPT is over expressed by tumoral cells, which take advantage from this to sustain growth rate and tumor progression. This has led to the initiation of numerous medicinal chemistry programs to develop NAMPT inhibitors in the context of oncology. More recently, however, it has been shown that NAMPT inhibitors do not solely target the tumor but also have an effect on the immune system. To add complexity, this enzyme can also be secreted by cells, and in the extracellular space it acts as a cytokine mainly through the activation of Toll like Receptor 4 (TLR4), although it has not been clarified yet if this is the only receptor responsible for its actions. While specific small molecules have been developed only against the intracellular form of NAMPT, growing evidences sustain the possibility to target the extracellular form. In this contribution, the most recent evidences on the medicinal chemistry of NAMPT will be reviewed, together with the key elements that sustain the hypothesis of NAMPT targeting and the drawbacks so far encountered.

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“…NAD levels can therefore restrict the activity of these two classes of NAD-metabolizing enzymes. Intriguingly, NAD can rapidly shuttle between different cellular compartments to reconstitute the pool that allows enzyme activation, as has recently been shown (46). When in the extracellular space, eNAD functions are linked to the modulation of cell surface P2X and P2Y purinergic receptor families, thereby acting in an apparently enzyme-independent way and eliciting pro-inflammatory immune responses (Figure 1).…”

Section: Intracellular and Extracellular Nad-metabolizing Machinerymentioning

confidence: 89%

The Extracellular NADome Modulates Immune Responses

et al. 2021

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The term NADome refers to the intricate network of intracellular and extracellular enzymes that regulate the synthesis or degradation of nicotinamide adenine dinucleotide (NAD) and to the receptors that engage it. Traditionally, NAD was linked to intracellular energy production through shuffling electrons between oxidized and reduced forms. However, recent data indicate that NAD, along with its biosynthetic and degrading enzymes, has a life outside of cells, possibly linked to immuno-modulating non-enzymatic activities. Extracellular NAD can engage puriginergic receptors triggering an inflammatory response, similar - to a certain extent – to what described for adenosine triphosphate (ATP). Likewise, NAD biosynthetic and degrading enzymes have been amply reported in the extracellular space, where they possess both enzymatic and non-enzymatic functions. Modulation of these enzymes has been described in several acute and chronic conditions, including obesity, cancer, inflammatory bowel diseases and sepsis. In this review, the role of the extracellular NADome will be discussed, focusing on its proposed role in immunomodulation, together with the different strategies for its targeting and their potential therapeutic impact.

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A nicotinamide phosphoribosyltransferase–GAPDH interaction sustains the stress-induced NMN/NAD+ salvage pathway in the nucleus

Cited by 22 publications

References 50 publications

NAMPT and NAPRT: Two Metabolic Enzymes With Key Roles in Inflammation

NAMPT and NAPRT: Two Metabolic Enzymes With Key Roles in Inflammation

Recent Advances in NAMPT Inhibitors: A Novel Immunotherapic Strategy

The Extracellular NADome Modulates Immune Responses

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