CD38

Last updated
CD38
Protein CD38 PDB 1yh3.png
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases CD38 , ADPRC1, ADPRC 1, CD38 molecule
External IDs OMIM: 107270 MGI: 107474 HomoloGene: 1345 GeneCards: CD38
EC number 2.4.99.20
Orthologs
SpeciesHumanMouse
Entrez

952

12494

Ensembl

ENSG00000004468

ENSMUSG00000029084

UniProt

P28907

P56528

RefSeq (mRNA)

NM_001775

NM_007646

RefSeq (protein)

NP_001766

NP_031672

Location (UCSC) Chr 4: 15.78 – 15.85 Mb Chr 5: 44.03 – 44.07 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

CD38 (cluster of differentiation 38), also known as cyclic ADP ribose hydrolase is a glycoprotein [5] found on the surface of many immune cells (white blood cells), including CD4 +, CD8 +, B lymphocytes and natural killer cells. CD38 also functions in cell adhesion, signal transduction and calcium signaling. [6]

In humans, the CD38 protein is encoded by the CD38 gene which is located on chromosome 4. [7] [8] CD38 is a paralog of CD157 , which is also located on chromosome 4 (4p15) in humans. [9]

History

CD38 was first identified in 1980 as a surface marker (cluster of differentiation) of thymus cell lymphocytes. [10] [11] In 1992 it was additionally described as a surface marker on B cells, monocytes, and natural killer cells (NK cells). [10] About the same time, CD38 was discovered to be not simply a marker of cell types, but an activator of B cells and T cells. [10] In 1992 the enzymatic activity of CD38 was discovered, having the capacity to synthesize the calcium-releasing second messengers cyclic ADP-ribose (cADPR) and nicotinic acid adenine dinucleotide phosphate (NAADP). [10]

Tissue distribution

CD38 is most frequently found on plasma B cells, followed by natural killer cells, followed by B cells and T cells, and then followed by a variety of cell types. [12]

Function

CD38 can function either as a receptor or as an enzyme. [13] As a receptor, CD38 can attach to CD31 on the surface of T cells, thereby activating those cells to produce a variety of cytokines. [13] CD38 activation cooperates with TRPM2 channels to initiate physiological responses such as cell volume regulation. [14]

CD38 is a multifunctional enzyme that catalyzes the synthesis of ADP ribose (ADPR) (97%) and cyclic ADP-ribose (cADPR) (3%) from NAD+. [15] [16] CD38 is thought to be a major regulator of NAD+ levels, its NADase activity is much higher than its function as an ADP-rybosyl-cyclase: for every 100 molecules of NAD+ converted to ADP ribose it generates one molecule of cADPR. [17] [15] When nicotinic acid is present under acidic conditions, CD38 can hydrolyze nicotinamide adenine dinucleotide phosphate (NADP+) to NAADP. [15] [18]

These reaction products are essential for the regulation of intracellular Ca2+. [19] CD38 occurs not only as an ectoenzyme on cell outer surfaces, but also occurs on the inner surface of cell membranes, facing the cytosol performing the same enzymatic functions. [20]

CD38 is believed to control or influence neurotransmitter release in the brain by producing cADPR. [21] CD38 within the brain enables release of the affiliative neuropeptide oxytocin. [22]

Like CD38, CD157 is a member of the ADP-ribosyl cyclase family of enzymes that catalyze the formation of cADPR from NAD+, although CD157 is a much weaker catalyst than CD38. [23] The SARM1 enzyme also catalyzes the formation of cADPR from NAD+, [20] but SARM1 elevates cADPR much more efficiently than CD38. [24]

Clinical significance

The loss of CD38 function is associated with impaired immune responses, metabolic disturbances, and behavioral modifications including social amnesia possibly related to autism. [19] [25]

CD31 on endothelial cells binds to the CD38 receptor on natural killer cells for those cells to attach to the endothelium. [26] [27] CD38 on leukocytes attaching to CD16 on endothelial cells allows for leukocyte binding to blood vessel walls, and the passage of leukocytes through blood vessel walls. [9]

The cytokine interferon gamma and the Gram negative bacterial cell wall component lipopolysaccharide induce CD38 expression on macrophages. [27] Interferon gamma strongly induces CD38 expression on monocytes. [19] The cytokine tumor necrosis factor strongly induces CD38 on airway smooth muscle cells inducing cADPR-mediated Ca2+, thereby increasing dysfunctional contractility resulting in asthma. [28]

The CD38 protein is a marker of cell activation. It has been connected to HIV infection, leukemias, myelomas, [29] solid tumors, type II diabetes mellitus and bone metabolism, as well as some genetically determined conditions.

CD38 increases airway contractility hyperresponsiveness, is increased in the lungs of asthmatic patients, and amplifies the inflammatory response of airway smooth muscle of those patients. [16]

Clinical application

CD38 inhibitors may be used as therapeutics for the treatment of asthma. [30]

CD38 has been used as a prognostic marker in leukemia. [31]

Daratumumab (Darzalex) which targets CD38 has been used in treating multiple myeloma. [32] [33]

The use of Daratumumab can interfere with pre-blood transfusion tests, as CD38 is weakly expressed on the surface of erythrocytes. Thus, a screening assay for irregular antibodies against red blood cell antigens or a direct immunoglobulin test can produce false-positive results. [34] This can be sidelined by either pretreatment of the erythrocytes with dithiothreitol (DTT) or by using an anti-CD38 antibody neutralizing agent, e.g. DaraEx.

Inhibitors

Aging studies

A gradual increase in CD38 has been implicated in the decline of NAD+ with age. [49] [50] Treatment of old mice with a specific CD38 inhibitor, 78c, prevents age-related NAD+ decline. [51] CD38 knockout mice have twice the levels of NAD+ and are resistant to age-associated NAD+ decline, [52] with dramatically increased NAD+ levels in major organs (liver, muscle, brain, and heart). [53] On the other hand, mice overexpressing CD38 exhibit reduced NAD+ and mitochondrial dysfunction. [52]

Macrophages are believed to be primarily responsible for the age-related increase in CD38 expression and NAD+ decline. [54] Cellular senescence of macrophages increases CD38 expression. [54] Macrophages accumulate in visceral fat and other tissues with age, leading to chronic inflammation. [55] The inflammatory transcription factor NF-κB and CD38 are mutually activating. [54] Secretions from senescent cells induce high levels of expression of CD38 on macrophages, which becomes the major cause of NAD+ depletion with age. [56]

Decline of NAD+ in the brain with age may be due to increased CD38 on astrocytes and microglia, leading to neuroinflammation and neurodegeneration. [21]

Related Research Articles

<span class="mw-page-title-main">Nicotinamide adenine dinucleotide</span> Chemical compound which is reduced and oxidized

Nicotinamide adenine dinucleotide (NAD) is a coenzyme central to metabolism. Found in all living cells, NAD is called a dinucleotide because it consists of two nucleotides joined through their phosphate groups. One nucleotide contains an adenine nucleobase and the other, nicotinamide. NAD exists in two forms: an oxidized and reduced form, abbreviated as NAD+ and NADH (H for hydrogen), respectively.

<span class="mw-page-title-main">Poly (ADP-ribose) polymerase</span> Family of proteins

Poly (ADP-ribose) polymerase (PARP) is a family of proteins involved in a number of cellular processes such as DNA repair, genomic stability, and programmed cell death.

<span class="mw-page-title-main">Cyclic ADP-ribose</span> Chemical compound

Cyclic ADP-ribose, frequently abbreviated as cADPR, is a cyclic adenine nucleotide (like cAMP) with two phosphate groups present on 5' OH of the adenosine (like ADP), further connected to another ribose at the 5' position, which, in turn, closes the cycle by glycosidic bonding to the nitrogen 1 (N1) of the same adenine base (whose position N9 has the glycosidic bond to the other ribose). The N1-glycosidic bond to adenine is what distinguishes cADPR from ADP-ribose (ADPR), the non-cyclic analog. cADPR is produced from nicotinamide adenine dinucleotide (NAD+) by ADP-ribosyl cyclases (EC 3.2.2.5) as part of a second messenger system.

<span class="mw-page-title-main">Nicotinic acid adenine dinucleotide phosphate</span> Chemical compound

Nicotinic acid adenine dinucleotide phosphate (NAADP) is a Ca2+-mobilizing second messenger synthesised in response to extracellular stimuli. Like its mechanistic cousins, IP3 and cyclic adenosine diphosphoribose (Cyclic ADP-ribose), NAADP binds to and opens Ca2+ channels on intracellular organelles, thereby increasing the intracellular Ca2+ concentration which, in turn, modulates sundry cellular processes (see Calcium signalling). Structurally, it is a dinucleotide that only differs from the house-keeping enzyme cofactor, NADP by a hydroxyl group (replacing the nicotinamide amino group) and yet this minor modification converts it into the most potent Ca2+-mobilizing second messenger yet described. NAADP acts across phyla from plants to humans.

<span class="mw-page-title-main">Adenosine diphosphate ribose</span> Chemical compound

Adenosine diphosphate ribose (ADPR) is an ester molecule formed into chains by the enzyme poly ADP ribose polymerase. ADPR is created from cyclic ADP-ribose (cADPR) by the CD38 enzyme using nicotinamide adenine dinucleotide (NAD+) as a cofactor.

<span class="mw-page-title-main">Histone-modifying enzymes</span> Type of enzymes

Histone-modifying enzymes are enzymes involved in the modification of histone substrates after protein translation and affect cellular processes including gene expression. To safely store the eukaryotic genome, DNA is wrapped around four core histone proteins, which then join to form nucleosomes. These nucleosomes further fold together into highly condensed chromatin, which renders the organism's genetic material far less accessible to the factors required for gene transcription, DNA replication, recombination and repair. Subsequently, eukaryotic organisms have developed intricate mechanisms to overcome this repressive barrier imposed by the chromatin through histone modification, a type of post-translational modification which typically involves covalently attaching certain groups to histone residues. Once added to the histone, these groups elicit either a loose and open histone conformation, euchromatin, or a tight and closed histone conformation, heterochromatin. Euchromatin marks active transcription and gene expression, as the light packing of histones in this way allows entry for proteins involved in the transcription process. As such, the tightly packed heterochromatin marks the absence of current gene expression.

<span class="mw-page-title-main">ADP-ribosylation</span> Addition of one or more ADP-ribose moieties to a protein.

ADP-ribosylation is the addition of one or more ADP-ribose moieties to a protein. It is a reversible post-translational modification that is involved in many cellular processes, including cell signaling, DNA repair, gene regulation and apoptosis. Improper ADP-ribosylation has been implicated in some forms of cancer. It is also the basis for the toxicity of bacterial compounds such as cholera toxin, diphtheria toxin, and others.

<span class="mw-page-title-main">PARP1</span> Mammalian protein found in Homo sapiens

Poly [ADP-ribose] polymerase 1 (PARP-1) also known as NAD+ ADP-ribosyltransferase 1 or poly[ADP-ribose] synthase 1 is an enzyme that in humans is encoded by the PARP1 gene. It is the most abundant of the PARP family of enzymes, accounting for 90% of the NAD+ used by the family. PARP1 is mostly present in cell nucleus, but cytosolic fraction of this protein was also reported.

<span class="mw-page-title-main">ADP-ribose diphosphatase</span>

ADP-ribose diphosphatase (EC 3.6.1.13) is an enzyme that catalyzes a hydrolysis reaction in which water nucleophilically attacks ADP-ribose to produce AMP and D-ribose 5-phosphate. Enzyme hydrolysis occurs by the breakage of a phosphoanhydride bond and is dependent on Mg2+ ions that are held in complex by the enzyme.

NAD<sup>+</sup> glycohydrolase Enzyme

In enzymology, a NAD+ glycohydrolase (EC 3.2.2.5) is an enzyme that catalyzes the chemical reaction

<span class="mw-page-title-main">ADP-ribosyl cyclase</span>

In enzymology, a ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase (EC 3.2.2.6) is a bifunctional enzyme that catalyzes the chemical reaction

<span class="mw-page-title-main">PARP4</span> Enzyme

Poly [ADP-ribose] polymerase 4 is an enzyme that in humans is encoded by the PARP4 gene.

<span class="mw-page-title-main">BST1</span> Protein-coding gene in the species Homo sapiens

Bst1 is an enzyme that in humans is encoded by the BST1 gene. CD157 is a paralog of CD38, both of which are located on chromosome 4 (4p15) in humans.

<span class="mw-page-title-main">PARP3</span> Protein-coding gene in the species Homo sapiens

Poly [ADP-ribose] polymerase 3 is an enzyme that in humans is encoded by the PARP3 gene.

<span class="mw-page-title-main">PARP2</span> Protein-coding gene in the species Homo sapiens

Poly [ADP-ribose] polymerase 2 is an enzyme that in humans is encoded by the PARP2 gene. It is one of the PARP family of enzymes.

<span class="mw-page-title-main">ADP-ribosylhydrolase 3</span> Protein-coding gene in the species Homo sapiens

(ADP-ribosyl)hydrolase 3 (ARH3) is an enzyme that in humans is encoded by the ADPRHL2 gene (also called ADPRS). This enzyme reverses the proteins’ post-translational addition of ADP-ribose to serine residues as part of the DNA damage response The enzyme is also known to cleave poly(ADP-ribose) polymers, 1''-O-acetyl-ADP-ribose and alpha-NAD+

<span class="mw-page-title-main">ADP-ribosylhydrolase</span>

In molecular biology, the (ADP-ribosyl)hydrolase (ARH) family contains enzymes which catalyses the hydrolysis of ADP-ribosyl modifications from proteins, nucleic acids and small molecules.

<span class="mw-page-title-main">Daratumumab</span> Monoclonal antibody

Daratumumab, sold under the brand name Darzalex, is an anti-cancer monoclonal antibody medication. It binds to CD38, which is overexpressed in multiple myeloma cells. Daratumumab was originally developed by Genmab, but it is now being jointly developed by Genmab along with the Johnson & Johnson subsidiary Janssen Biotech, which acquired worldwide commercialization rights to the drug from Genmab.

<span class="mw-page-title-main">Isatuximab</span> Monoclonal antibody

Isatuximab, sold under the brand name Sarclisa, is a monoclonal antibody (mAb) medication for the treatment of multiple myeloma.

<span class="mw-page-title-main">SARM1</span> Protein-coding gene in the species Homo sapiens

Sterile alpha and TIR motif containing 1 Is an enzyme that in humans is encoded by the SARM1 gene. It is the most evolutionarily conserved member of the Toll/Interleukin receptor-1 (TIR) family. SARM1's TIR domain has intrinsic NADase enzymatic activity that is highly conserved from archaea, plants, nematode worms, fruit flies, and humans. In mammals, SARM1 is highly expressed in neurons, where it resides in both cell bodies and axons, and can be associated with mitochondria.

References

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  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000029084 – Ensembl, May 2017
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