The CD38 glycohydrolase and the NAD sink: implications for pathological conditions

Abstract

Nicotinamide adenine dinucleotide (NAD) acts as a cofactor in several oxidation-reduction (redox) reactions and is a substrate for a number of nonredox enzymes. NAD is fundamental to a variety of cellular processes including energy metabolism, cell signaling, and epigenetics. NAD homeostasis appears to be of paramount importance to health span and longevity, and its dysregulation is associated with multiple diseases. NAD metabolism is dynamic and maintained by synthesis and degradation. The enzyme CD38, one of the main NAD-consuming enzymes, is a key component of NAD homeostasis. The majority of CD38 is localized in the plasma membrane with its catalytic domain facing the extracellular environment, likely for the purpose of controlling systemic levels of NAD. Several cell types express CD38, but its expression predominates on endothelial cells and immune cells capable of infiltrating organs and tissues. Here we review potential roles of CD38 in health and disease and postulate ways in which CD38 dysregulation causes changes in NAD homeostasis and contributes to the pathophysiology of multiple conditions. Indeed, in animal models the development of infectious diseases, autoimmune disorders, fibrosis, metabolic diseases, and age-associated diseases including cancer, heart disease, and neurodegeneration are associated with altered CD38 enzymatic activity. Many of these conditions are modified in CD38-deficient mice or by blocking CD38 NADase activity. In diseases in which CD38 appears to play a role, CD38-dependent NAD decline is often a common denominator of pathophysiology. Thus, understanding dysregulation of NAD homeostasis by CD38 may open new avenues for the treatment of human diseases.

Keywords: CD38; NAD metabolism; diseases.

Figure 1.

Diseases associated with CD38 and/or nicotinamide adenine dinucleotide (NAD) dysfunction. Asterisks indicate diseases in which CD38 and NAD metabolism play a role in pathophysiology but the link between CD38 and NAD dysregulation in these diseases is yet to be established. GI, gastrointestinal.

Figure 2.

Nicotinamide adenine dinucleotide (NAD) pathways: synthesis, degradation, and excretion. Overview of the pathways related to NAD metabolism. 2PY, N-methyl-2-pyridone-5-carboxamide; 4PY, N-methyl-4-pyridone-3-carboxamide; ACMS, 2-amino-3-carboxymuconic acid semialdehyde; ADPR, ADP-ribose; AFMID, arylformamidase; AOX, aldehyde oxidase; Cyp2E1, cytochrome P-450 2E1; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; HAAO, 3-hydroxyanthranilate 3,4-dioxygenase; IDO, indoleamine 2,3-dioxygenase; KMO, kynurenine 3-monooxygenase; KYNU, kynureninase; M-NAM, methyl nicotinamide; NA, nicotinic acid; NaAD, nicotinic acid adenine dinucleotide; NAD, nicotinamide adenine dinucleotide; NAM, nicotinamide; NaMN, nicotinic acid mononucleotide; NAMPT, nicotinamide phosphoribosyltransferase; NaPRT1, nicotinic acid phosphoribosyltransferase 1; NMN, nicotinamide mononucleotide; NMNAT1, nicotinamide/nicotinic acid mononucleotide adenylyltransferase 1; NNMT, nicotinamide N-methyltransferase; NR, nicotinamide riboside; PARP, poly(ADP-ribose) polymerase; PRPP, phosphoribosyl pyrophosphate; QPRT, quinolinate phosphoribosyl transferase; SARM1, sterile α and TIR motif-containing protein 1; TPO, tryptophan 2,3-dioxygenase. Figure modified from Chini et al. (319) with permission from Cell Metabolism.

Figure 3.

Interplay between CD38, nicotinamide adenine dinucleotide (NAD) decline, and inflammation. Inflammatory signals induce the recruitment of CD38⁺ cells to a specific site, where increased CD38 activity leads to NAD decline, inhibition of sirtuins and epigenetic changes, altered gene expression, and metabolic stress.

Figure 4.

Ischemia and CD38. During ischemia there is increased expression of CD38 on endothelial cells in the vasculature, resulting in nicotinamide adenine dinucleotide (NAD) decline, downregulation of Sirt1, and endothelial dysfunction. NAD boosting by supplementation with NAD precursors has a protective effect on endothelial function. Although not yet extensively explored, CD38 inhibition could be a target to treat ischemia-induced endothelial dysfunction. NAM, nicotinamide; NMN, nicotinamide mononucleotide; NR, nicotinamide riboside. Used with permission of Mayo Foundation for Medical Education and Research, all rights reserved.