CD38

CD38
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 4TMF, 1YH3, 1ZVM, 2EF1, 2HCT, 2I65, 2I66, 2I67, 2O3Q, 2O3R, 2O3S, 2O3T, 2O3U, 2PGJ, 2PGL, 3DZF, 3DZG, 3DZH, 3DZI, 3DZJ, 3DZK, 3F6Y, 3I9M, 3I9N, 3OFS, 3RAJ, 3ROK, 3ROM, 3ROP, 3ROQ, 3U4H, 3U4I, 4CMH, 4F45, 4F46, 4OGW, 4XJS, 4XJT, 5F1K, 5F1O, 5F21
Identifiers
Aliases	CD38 , ADPRC1, ADPRC 1, CD38 molecule
External IDs	OMIM: 107270; MGI: 107474; HomoloGene: 1345; GeneCards: CD38; OMA:CD38 - orthologs
EC number	2.4.99.20
Gene location (Human) Chr. Chromosome 4 (human) [1] Band 4p15.32 Start 15,778,275 bp [1] End 15,853,232 bp [1]
Gene location (Mouse) Chr. Chromosome 5 (mouse) [2] Band 5 B3|5 23.85 cM Start 44,025,895 bp [2] End 44,069,717 bp [2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in seminal vesicula bone marrow cells lymph node thymus appendix spleen bronchial epithelial cell gonad granulocyte muscle of thigh Top expressed in stroma of bone marrow left colon seminal vesicula spleen mesenteric lymph nodes Paneth cell jejunum lumbar subsegment of spinal cord left lung lobe duodenum More reference expression data BioGPS More reference expression data
Gene ontology Molecular function transferase activity hydrolase activity, acting on glycosyl bonds NAD(P)+ nucleosidase activity hydrolase activity NAD+ nucleotidase, cyclic ADP-ribose generating NAD+ nucleosidase activity phosphorus-oxygen lyase activity identical protein binding Cellular component integral component of membrane membrane intracellular membrane-bounded organelle cell surface extracellular exosome nucleus plasma membrane basolateral plasma membrane secretory granule membrane Biological process B cell receptor signaling pathway response to cytokine response to estradiol response to interleukin-1 response to hypoxia response to retinoic acid positive regulation of cytosolic calcium ion concentration response to progesterone female pregnancy negative regulation of apoptotic process response to hydroperoxide positive regulation of transcription, DNA-templated positive regulation of cell growth positive regulation of B cell proliferation positive regulation of vasoconstriction long-term depression apoptotic signaling pathway response to hormone negative regulation of transcription, DNA-templated signal transduction positive regulation of insulin secretion negative regulation of bone resorption NAD metabolic process positive regulation of cell population proliferation negative regulation of neuron projection development artery smooth muscle contraction Sources:Amigo / QuickGO
Orthologs Species Human Mouse 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 CD31 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. D-REX or DaraEx.

Inhibitors

• Cassic acid (Rhein) ^[35]
• CD38-IN-78c ^[36]
• Chrysanthemin (Kuromanin) ^[37]
• compound 1ai ^[38]
• compound 1am ^{[39] [40]}
• Daratumumab ^[41]
• Isatuximab ^[42]
• Felzartamab (MOR202) ^[43]
• apigenin ^[44]
• Luteolinidin ^[45]
• MK-0159 ^{[46] [47]}
• TNB-738 ^[48]

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]

References

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Further reading

• States DJ, Walseth TF, Lee HC (December 1992). "Similarities in amino acid sequences of Aplysia ADP-ribosyl cyclase and human lymphocyte antigen CD38". Trends in Biochemical Sciences. 17 (12): 495. doi:10.1016/0968-0004(92)90337-9. PMID   1471258.
• Malavasi F, Funaro A, Roggero S, Horenstein A, Calosso L, Mehta K (March 1994). "Human CD38: a glycoprotein in search of a function". Immunology Today. 15 (3): 95–7. doi:10.1016/0167-5699(94)90148-1. PMID   8172650.
• Guse AH (May 1999). "Cyclic ADP-ribose: a novel Ca2+-mobilising second messenger". Cellular Signalling. 11 (5): 309–16. doi:10.1016/S0898-6568(99)00004-2. PMID   10376802.
• Funaro A, Malavasi F (1999). "Human CD38, a surface receptor, an enzyme, an adhesion molecule and not a simple marker". Journal of Biological Regulators and Homeostatic Agents. 13 (1): 54–61. PMID   10432444.
• Mallone R, Perin PC (2006). "Anti-CD38 autoantibodies in type? diabetes". Diabetes/Metabolism Research and Reviews. 22 (4): 284–94. doi:10.1002/dmrr.626. PMC   2763400 . PMID   16544364.
• Partidá-Sánchez S, Rivero-Nava L, Shi G, Lund FE (2007). "CD38: an ecto-enzyme at the crossroads of innate and adaptive immune responses". Crossroads between Innate and Adaptive Immunity . Advances in Experimental Medicine and Biology. Vol. 590. pp.  171–83. doi:10.1007/978-0-387-34814-8_12. ISBN   978-0-387-34813-1. PMID   17191385.
• Jackson DG, Bell JI (April 1990). "Isolation of a cDNA encoding the human CD38 (T10) molecule, a cell surface glycoprotein with an unusual discontinuous pattern of expression during lymphocyte differentiation". Journal of Immunology. 144 (7): 2811–5. doi: 10.4049/jimmunol.144.7.2811 . PMID   2319135. S2CID   29082806.
• Dianzani U, Bragardo M, Buonfiglio D, Redoglia V, Funaro A, Portoles P, et al. (May 1995). "Modulation of CD4 lateral interaction with lymphocyte surface molecules induced by HIV-1 gp120". European Journal of Immunology. 25 (5): 1306–11. doi:10.1002/eji.1830250526. PMID   7539755. S2CID   37717142.
• Nakagawara K, Mori M, Takasawa S, Nata K, Takamura T, Berlova A, et al. (1995). "Assignment of CD38, the gene encoding human leukocyte antigen CD38 (ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase), to chromosome 4p15". Cytogenetics and Cell Genetics. 69 (1–2): 38–9. doi:10.1159/000133933. PMID   7835083.
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External links

• CD38+Antigens at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
• Human CD38 genome location and CD38 gene details page in the UCSC Genome Browser .
• GeneCard CD38
• Overview of all the structural information available in the PDB for UniProt : P28907 (ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase 1) at the PDBe-KB .
• CD38