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CD38

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CD38
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesCD38, ADPRC1, ADPRC 1, CD38 molecule
External IDsOMIM: 107270; MGI: 107474; HomoloGene: 1345; GeneCards: CD38; OMA:CD38 - orthologs
EC number2.4.99.20
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 MbChr 5: 44.03 – 44.07 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/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

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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

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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

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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

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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

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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

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Aging studies

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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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  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000004468 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000029084 – Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ Orciani M, Trubiani O, Guarnieri S, Ferrero E, Di Primio R (October 2008). "CD38 is constitutively expressed in the nucleus of human hematopoietic cells". Journal of Cellular Biochemistry. 105 (3): 905–12. doi:10.1002/jcb.21887. PMID 18759251. S2CID 44430455.
  6. ^ "Entrez Gene: CD38 CD38 molecule".
  7. ^ 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.
  8. ^ Nata K, Takamura T, Karasawa T, Kumagai T, Hashioka W, Tohgo A, et al. (February 1997). "Human gene encoding CD38 (ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase): organization, nucleotide sequence and alternative splicing". Gene. 186 (2): 285–92. doi:10.1016/S0378-1119(96)00723-8. PMID 9074508.
  9. ^ a b Quarona V, Zaccarello G, Chillemi A (2013). "CD38 and CD157: a long journey from activation markers to multifunctional molecules". Cytometry Part B. 84 (4): 207–217. doi:10.1002/cyto.b.21092. hdl:2318/134656. PMID 23576305. S2CID 205732787.
  10. ^ a b c d Lee H, ed. (2002). A Natural History of the Human CD38 Gene. In:Cyclic ADP-Ribose and NAADP. Springer Publishing. doi:10.1007/978-1-4615-0269-2_4. ISBN 978-1-4613-4996-9.
  11. ^ Reinherz EL, Kung PC, Schlossman SF (1980). "Discrete stages of human intrathymic differentiation: analysis of normal thymocytes and leukemic lymphoblasts of T-cell lineage". Proceedings of the National Academy of Sciences of the United States of America. 77 (3): 1588–1592. Bibcode:1980PNAS...77.1588R. doi:10.1073/pnas.77.3.1588. PMC 348542. PMID 6966400.
  12. ^ van de Donk N, Richardson PG, Malavasi F (2018). "CD38 antibodies in multiple myeloma: back to the future". Blood. 131 (1): 13–29. doi:10.1182/blood-2017-06-740944. PMID 29118010.
  13. ^ a b Nooka AK, Kaufman JL, Hofmeister CC, Joseph NS (2019). "Daratumumab in multiple myeloma". Cancer. 125 (14): 2364–2382. doi:10.1002/cncr.32065. PMID 30951198. S2CID 96435958.
  14. ^ Numata T, Sato K, Christmann J, Marx R, Mori Y, Okada Y, et al. (2012). "The ΔC splice-variant of TRPM2 is the hypertonicity-induced cation channel in HeLa cells, and the ecto-enzyme CD38 mediates its activation". J. Physiol. 590 (5): 1121–1138. doi:10.1113/jphysiol.2011.220947. PMC 3381820. PMID 22219339.
  15. ^ a b c Kar A, Mehrotra S, Chatterjee S (2020). "CD38: T Cell Immuno-Metabolic Modulator". Cells. 9 (7): 1716. doi:10.3390/cells9071716. PMC 7408359. PMID 32709019.
  16. ^ a b Guedes A, Dileepan M, Jude JA, Kannan MS (2020). "Role of CD38/cADPR signaling in obstructive pulmonary diseases". Current Opinion in Pharmacology. 51: 29–33. doi:10.1016/j.coph.2020.04.007. PMC 7529733. PMID 32480246.
  17. ^ Braidy N, Berg J, Clement J, Sachdev P (2019). "Role of Nicotinamide Adenine Dinucleotide and Related Precursors as Therapeutic Targets for Age-Related Degenerative Diseases: Rationale, Biochemistry, Pharmacokinetics, and Outcomes". Antioxidants & Redox Signaling. 10 (2): 251–294. doi:10.1089/ars.2017.7269. PMC 6277084. PMID 29634344.
  18. ^ Chini EN, Chini CC, Kato I, Takasawa S, Okamoto H (February 2002). "CD38 is the major enzyme responsible for synthesis of nicotinic acid-adenine dinucleotide phosphate in mammalian tissues". The Biochemical Journal. 362 (Pt 1): 125–30. doi:10.1042/0264-6021:3620125. PMC 1222368. PMID 11829748.
  19. ^ a b c Malavasi F, Deaglio S, Funaro A, Ferrero E, Horenstein AL, Ortolan E, et al. (July 2008). "Evolution and function of the ADP ribosyl cyclase/CD38 gene family in physiology and pathology". Physiological Reviews. 88 (3): 841–86. doi:10.1152/physrev.00035.2007. PMID 18626062.
  20. ^ a b Lee HC, Zhao YJ (2019). "Resolving the topological enigma in Ca 2+ signaling by cyclic ADP-ribose and NAADP". Journal of Biological Chemistry. 294 (52): 19831–19843. doi:10.1074/jbc.REV119.009635. PMC 6937575. PMID 31672920.
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  24. ^ Zhao ZY, Xie XJ, Li WH, Zhao YJ (2016). "A Cell-Permeant Mimetic of NMN Activates SARM1 to Produce Cyclic ADP-Ribose and Induce Non-apoptotic Cell Death". iScience. 15: 452–466. doi:10.1016/j.isci.2019.05.001. PMC 6531917. PMID 31128467.
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  27. ^ a b Glaría E, Valledor AF (2020). "Roles of CD38 in the Immune Response to Infection". Cells. 9 (1): 228. doi:10.3390/cells9010228. PMC 7017097. PMID 31963337.
  28. ^ Deshpande DA, Guedes A, Graeff R, Dogan S (2018). "CD38/cADPR Signaling Pathway in Airway Disease: Regulatory Mechanisms". Mediators of Inflammation. 2018: 8942042. doi:10.1155/2018/8942042. PMC 5821947. PMID 29576747.
  29. ^ Marlein CR, Piddock RE, Mistry JJ, Zaitseva L, Hellmich C, Horton RH, et al. (January 2019). "CD38-driven mitochondrial trafficking promotes bioenergetic plasticity in multiple myeloma". Cancer Research. 79 (9): 2285–2297. doi:10.1158/0008-5472.CAN-18-0773. PMID 30622116.
  30. ^ Deshpande DA, Guedes AG, Lund FE, Kannan MS (2017). "CD38 in the pathogenesis of allergic airway disease: Potential therapeutic targets". Pharmacology & Therapeutics. 172: 116–126. doi:10.1016/j.pharmthera.2016.12.002. PMC 5346344. PMID 27939939.
  31. ^ Deaglio S, Mehta K, Malavasi F (January 2001). "Human CD38: a (r)evolutionary story of enzymes and receptors". Leukemia Research. 25 (1): 1–12. doi:10.1016/S0145-2126(00)00093-X. PMID 11137554.
  32. ^ McKeage K (February 2016). "Daratumumab: First Global Approval". Drugs. 76 (2): 275–81. doi:10.1007/s40265-015-0536-1. PMID 26729183. S2CID 11977989.
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  34. ^ de Vooght KM, Lozano M, Bueno JL, Alarcon A, Romera I, Suzuki K, et al. (May 2018). "Vox Sanguinis International Forum on typing and matching strategies in patients on anti-CD38 monoclonal therapy: summary". Vox Sanguinis. 113 (5): 492–498. doi:10.1111/vox.12653. PMID 29781081. S2CID 29156699.
  35. ^ Blacher E, Ben Baruch B, Levy A, Geva N, Green KD, Garneau-Tsodikova S, et al. (March 2015). "Inhibition of glioma progression by a newly discovered CD38 inhibitor". International Journal of Cancer. 136 (6): 1422–33. doi:10.1002/ijc.29095. PMID 25053177. S2CID 41844152.
  36. ^ Tarragó MG, Chini CC, Kanamori KS, Warner GM, Caride A, de Oliveira GC, et al. (May 2018). "+ Decline". Cell Metabolism. 27 (5): 1081–1095.e10. doi:10.1016/j.cmet.2018.03.016. PMC 5935140. PMID 29719225.
  37. ^ Kellenberger E, Kuhn I, Schuber F, Muller-Steffner H (July 2011). "Flavonoids as inhibitors of human CD38". Bioorganic & Medicinal Chemistry Letters. 21 (13): 3939–42. doi:10.1016/j.bmcl.2011.05.022. PMID 21641214.
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  39. ^ Deaton DN, Haffner CD, Henke BR, Jeune MR, Shearer BG, Stewart EL, et al. (May 2018). "2,4-Diamino-8-quinazoline carboxamides as novel, potent inhibitors of the NAD hydrolyzing enzyme CD38: Exploration of the 2-position structure-activity relationships". Bioorganic & Medicinal Chemistry. 26 (8): 2107–2150. doi:10.1016/j.bmc.2018.03.021. PMID 29576271.
  40. ^ Sepehri B, Ghavami R (January 2019). "Design of new CD38 inhibitors based on CoMFA modelling and molecular docking analysis of 4‑amino-8-quinoline carboxamides and 2,4-diamino-8-quinazoline carboxamides". SAR and QSAR in Environmental Research. 30 (1): 21–38. Bibcode:2019SQER...30...21S. doi:10.1080/1062936X.2018.1545695. PMID 30489181. S2CID 54158219.
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Further reading

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