Biology:CD38

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Short description: Protein-coding gene in the species Homo sapiens


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

CD38 (cluster of differentiation 38), also known as cyclic ADP ribose hydrolase is a glycoprotein[1] 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.[2]

In humans, the CD38 protein is encoded by the CD38 gene which is located on chromosome 4.[3][4] CD38 is a paralog of CD157, which is also located on chromosome 4 (4p15) in humans.[5]

History

CD38 was first identified in 1980 as a surface marker (cluster of differentiation) of thymus cell lymphocytes.[6][7] In 1992 it was additionally described as a surface marker on B cells, monocytes, and natural killer cells (NK cells).[6] 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.[6] 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).[6]

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.[8]

Function

CD38 can function either as a receptor or as an enzyme.[9] As a receptor, CD38 can attach to CD31 on the surface of T cells, thereby activating those cells to produce a variety of cytokines.[9] CD38 activation cooperates with TRPM2 channels to initiate physiological responses such as cell volume regulation.[10]

CD38 is a multifunctional enzyme that catalyzes the synthesis of ADP ribose (ADPR) (97%) and cyclic ADP-ribose (cADPR) (3%) from NAD+.[11][12] 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.[13][11] When nicotinic acid is present under acidic conditions, CD38 can hydrolyze nicotinamide adenine dinucleotide phosphate (NADP+) to NAADP.[11][14]

These reaction products are essential for the regulation of intracellular Ca2+.[15] 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.[16]

CD38 is believed to control or influence neurotransmitter release in the brain by producing cADPR.[17] CD38 within the brain enables release of the affiliative neuropeptide oxytocin.[18]

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.[19] The SARM1 enzyme also catalyzes the formation of cADPR from NAD+,[16] but SARM1 elevates cADPR much more efficiently than CD38.[20]

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.[15][21]

CD31 on endothelial cells binds to the CD38 receptor on natural killer cells for those cells to attach to the endothelium.[22][23] 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.[5]

The cytokine interferon gamma and the Gram negative bacterial cell wall component lipopolysaccharide induce CD38 expression on macrophages.[23] Interferon gamma strongly induces CD38 expression on monocytes.[15] The cytokine tumor necrosis factor strongly induces CD38 on airway smooth muscle cells inducing cADPR-mediated Ca2+, thereby increasing dysfunctional contractility resulting in asthma.[24]

The CD38 protein is a marker of cell activation. It has been connected to HIV infection, leukemias, myelomas,[25] 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.[12]

Increased expression of CD38 is an unfavourable prognostic [26] marker in chronic lymphocytic leukemia and is associated with increased disease progression.

CD38 is upregulated on plasmacytoid dendritic cells (pDCs) in vivo during human influenza infection and blocking CD38 prevents the ability of pDCs to produce type I interferon in vitro.[27]

Clinical application

CD38 inhibitors may be used as therapeutics for the treatment of asthma.[28]

CD38 has been used as a prognostic marker in leukemia.[29]

Daratumumab (Darzalex) which targets CD38 has been used in treating multiple myeloma.[30][31]

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.[32] 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.[47][48] Treatment of old mice with a specific CD38 inhibitor, 78c, prevents age-related NAD+ decline.[49] CD38 knockout mice have twice the levels of NAD+ and are resistant to age-associated NAD+ decline,[50] with dramatically increased NAD+ levels in major organs (liver, muscle, brain, and heart).[51] On the other hand, mice overexpressing CD38 exhibit reduced NAD+ and mitochondrial dysfunction.[50]

Macrophages are believed to be primarily responsible for the age-related increase in CD38 expression and NAD+ decline.[52] Cellular senescence of macrophages increases CD38 expression.[52] Macrophages accumulate in visceral fat and other tissues with age, leading to chronic inflammation.[53] The inflammatory transcription factor NF-κB and CD38 are mutually activating.[52] Secretions from senescent cells induce high levels of expression of CD38 on macrophages, which becomes the major cause of NAD+ depletion with age.[54]

Decline of NAD+ in the brain with age may be due to increased CD38 on astrocytes and microglia, leading to neuroinflammation and neurodegeneration.[17]

References

  1. ↑ "CD38 is constitutively expressed in the nucleus of human hematopoietic cells". Journal of Cellular Biochemistry 105 (3): 905–12. October 2008. doi:10.1002/jcb.21887. PMID 18759251. 
  2. ↑ "Entrez Gene: CD38 CD38 molecule". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=952. 
  3. ↑ "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. April 1990. doi:10.4049/jimmunol.144.7.2811. PMID 2319135. 
  4. ↑ "Human gene encoding CD38 (ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase): organization, nucleotide sequence and alternative splicing". Gene 186 (2): 285–92. February 1997. doi:10.1016/S0378-1119(96)00723-8. PMID 9074508. 
  5. ↑ 5.0 5.1 "CD38 and CD157: a long journey from activation markers to multifunctional molecules". Cytometry Part B 84 (4): 207–217. 2013. doi:10.1002/cyto.b.21092. PMID 23576305. 
  6. ↑ 6.0 6.1 6.2 6.3 Lee, H.C., 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. 
  7. ↑ "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. 1980. doi:10.1073/pnas.77.3.1588. PMID 6966400. Bibcode: 1980PNAS...77.1588R. 
  8. ↑ "CD38 antibodies in multiple myeloma: back to the future". Blood 131 (1): 13–29. 2018. doi:10.1182/blood-2017-06-740944. PMID 29118010. 
  9. ↑ 9.0 9.1 "Daratumumab in multiple myeloma". Cancer 125 (14): 2364–2382. 2019. doi:10.1002/cncr.32065. PMID 30951198. 
  10. ↑ "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. 2012. doi:10.1113/jphysiol.2011.220947. PMID 22219339. 
  11. ↑ 11.0 11.1 11.2 "CD38: T Cell Immuno-Metabolic Modulator". Cells 9 (7): 1716. 2020. doi:10.3390/cells9071716. PMID 32709019. 
  12. ↑ 12.0 12.1 "Role of CD38/cADPR signaling in obstructive pulmonary diseases". Current Opinion in Pharmacology 51: 29–33. 2020. doi:10.1016/j.coph.2020.04.007. PMID 32480246. 
  13. ↑ "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. 2019. doi:10.1089/ars.2017.7269. PMID 29634344. 
  14. ↑ "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. February 2002. doi:10.1042/0264-6021:3620125. PMID 11829748. 
  15. ↑ 15.0 15.1 15.2 "Evolution and function of the ADP ribosyl cyclase/CD38 gene family in physiology and pathology". Physiological Reviews 88 (3): 841–86. July 2008. doi:10.1152/physrev.00035.2007. PMID 18626062. 
  16. ↑ 16.0 16.1 "Resolving the topological enigma in Ca 2+ signaling by cyclic ADP-ribose and NAADP". Journal of Biological Chemistry 294 (52): 19831–19843. 2019. doi:10.1074/jbc.REV119.009635. PMID 31672920. 
  17. ↑ 17.0 17.1 "CD38 in Neurodegeneration and Neuroinflammation". Cells 9 (2): 471. 2020. doi:10.3390/cells9020471. PMID 32085567. 
  18. ↑ "A Novel Role of CD38 and Oxytocin as Tandem Molecular Moderators of Human Social Behavior". Neuroscience & Biobehavioral Reviews 115: 251–272. 2020. doi:10.1016/j.neubiorev.2020.04.013. PMID 32360414. https://discovery.dundee.ac.uk/en/publications/7b019211-b792-409d-aed3-c54512271345. 
  19. ↑ "CD38, CD157, and RAGE as Molecular Determinants for Social Behavior". Cells 9 (1): 62. 2019. doi:10.3390/cells9010062. PMID 31881755. 
  20. ↑ "A Cell-Permeant Mimetic of NMN Activates SARM1 to Produce Cyclic ADP-Ribose and Induce Non-apoptotic Cell Death". iScience 15: 452–466. 2016. doi:10.1016/j.isci.2019.05.001. PMID 31128467. 
  21. ↑ "Social memory, amnesia, and autism: brain oxytocin secretion is regulated by NAD+ metabolites and single nucleotide polymorphisms of CD38". Neurochemistry International 61 (6): 828–38. November 2012. doi:10.1016/j.neuint.2012.01.030. PMID 22366648. https://kanazawa-u.repo.nii.ac.jp/?action=repository_uri&item_id=30999. 
  22. ↑ "NK cells and CD38: Implication for (Immuno)Therapy in Plasma Cell Dyscrasias". Cells 9 (3): 768. 2020. doi:10.3390/cells9030768. PMID 32245149. 
  23. ↑ 23.0 23.1 "Roles of CD38 in the Immune Response to Infection". Cells 9 (1): 228. 2020. doi:10.3390/cells9010228. PMID 31963337. 
  24. ↑ "CD38/cADPR Signaling Pathway in Airway Disease: Regulatory Mechanisms". Mediators of Inflammation 2018: 8942042. 2018. doi:10.1155/2018/8942042. PMID 29576747. 
  25. ↑ "CD38-driven mitochondrial trafficking promotes bioenergetic plasticity in multiple myeloma". Cancer Research 79 (9): 2285–2297. January 2019. doi:10.1158/0008-5472.CAN-18-0773. PMID 30622116. 
  26. ↑ Dürig, J.; Naschar, M.; Schmücker, U.; Renzing-Köhler, K.; Hölter, T.; Hüttmann, A.; Dührsen, U. (January 2002). "CD38 expression is an important prognostic marker in chronic lymphocytic leukaemia" (in en). Leukemia 16 (1): 30–35. doi:10.1038/sj.leu.2402339. ISSN 1476-5551. https://www.nature.com/articles/2402339. 
  27. ↑ "Landscape of coordinated immune responses to H1N1 challenge in humans". The Journal of Clinical Investigation 130 (11): 5800–5816. November 2020. doi:10.1172/JCI137265. PMID 33044226. 
  28. ↑ "CD38 in the pathogenesis of allergic airway disease: Potential therapeutic targets". Pharmacology & Therapeutics 172: 116–126. 2017. doi:10.1016/j.pharmthera.2016.12.002. PMID 27939939. 
  29. ↑ "Human CD38: a (r)evolutionary story of enzymes and receptors". Leukemia Research 25 (1): 1–12. January 2001. doi:10.1016/S0145-2126(00)00093-X. PMID 11137554. 
  30. ↑ "Daratumumab: First Global Approval". Drugs 76 (2): 275–81. February 2016. doi:10.1007/s40265-015-0536-1. PMID 26729183. 
  31. ↑ "Daratumumab: monoclonal antibody therapy to treat multiple myeloma". Drugs of Today 52 (10): 551–560. October 2016. doi:10.1358/dot.2016.52.10.2543308. PMID 27910963. 
  32. ↑ "Vox Sanguinis International Forum on typing and matching strategies in patients on anti-CD38 monoclonal therapy: summary". Vox Sanguinis 113 (5): 492–498. May 2018. doi:10.1111/vox.12653. PMID 29781081. 
  33. ↑ "Inhibition of glioma progression by a newly discovered CD38 inhibitor". International Journal of Cancer 136 (6): 1422–33. March 2015. doi:10.1002/ijc.29095. PMID 25053177. 
  34. ↑ "+ Decline". Cell Metabolism 27 (5): 1081–1095.e10. May 2018. doi:10.1016/j.cmet.2018.03.016. PMID 29719225. 
  35. ↑ "Flavonoids as inhibitors of human CD38". Bioorganic & Medicinal Chemistry Letters 21 (13): 3939–42. July 2011. doi:10.1016/j.bmcl.2011.05.022. PMID 21641214. 
  36. ↑ "Discovery of 4-Amino-8-quinoline Carboxamides as Novel, Submicromolar Inhibitors of NAD-Hydrolyzing Enzyme CD38". Journal of Medicinal Chemistry 58 (17): 7021–56. September 2015. doi:10.1021/acs.jmedchem.5b00992. PMID 26267483. 
  37. ↑ "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. May 2018. doi:10.1016/j.bmc.2018.03.021. PMID 29576271. 
  38. ↑ "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. January 2019. doi:10.1080/1062936X.2018.1545695. PMID 30489181. 
  39. ↑ "Daratumumab for the treatment of AL amyloidosis". Leukemia & Lymphoma 60 (2): 295–301. February 2019. doi:10.1080/10428194.2018.1485914. PMID 30033840. 
  40. ↑ "Sarclisa EPAR". 29 July 2021. https://www.ema.europa.eu/en/medicines/human/EPAR/sarclisa. 
  41. ↑ "MOR202, a novel anti-CD38 monoclonal antibody, in patients with relapsed or refractory multiple myeloma: a first-in-human, multicentre, phase 1-2a trial". The Lancet. Haematology 7 (5): e381–e394. May 2020. doi:10.1016/S2352-3026(19)30249-2. PMID 32171061. 
  42. ↑ "Flavonoid apigenin is an inhibitor of the NAD+ ase CD38: implications for cellular NAD+ metabolism, protein acetylation, and treatment of metabolic syndrome". Diabetes 62 (4): 1084–1093. April 2013. doi:10.2337/db12-1139. PMID 23172919. 
  43. ↑ "Luteolinidin Protects the Postischemic Heart through CD38 Inhibition with Preservation of NAD(P)(H)". The Journal of Pharmacology and Experimental Therapeutics 361 (1): 99–108. April 2017. doi:10.1124/jpet.116.239459. PMID 28108596. 
  44. ↑ "Orally Bioavailable Enzymatic Inhibitor of CD38, MK-0159, Protects against Ischemia/Reperfusion Injury in the Murine Heart". Journal of Medicinal Chemistry 65 (13): 9418–9446. July 2022. doi:10.1021/acs.jmedchem.2c00688. PMID 35762533. 
  45. ↑ "CD38 reduces mitochondrial fitness and cytotoxic T cell response against viral infection in lupus patients by suppressing mitophagy". Science Advances 8 (24): eabo4271. June 2022. doi:10.1126/sciadv.abo4271. PMID 35704572. Bibcode: 2022SciA....8O4271C. 
  46. ↑ "TNB-738, a biparatopic antibody, boosts intracellular NAD+ by inhibiting CD38 ecto-enzyme activity". mAbs 14 (1): 2095949. 2022. doi:10.1080/19420862.2022.2095949. PMID 35867844. 
  47. ↑ "CD38 Dictates Age-Related NAD Decline and Mitochondrial Dysfunction through an SIRT3-Dependent Mechanism". Cell Metabolism 23 (6): 1127–1139. June 2016. doi:10.1016/j.cmet.2016.05.006. PMID 27304511. 
  48. ↑ "Why NAD(+) Declines during Aging: It's Destroyed". Cell Metabolism 23 (6): 965–966. June 2016. doi:10.1016/j.cmet.2016.05.022. PMID 27304496. 
  49. ↑ "A Potent and Specific CD38 Inhibitor Ameliorates Age-Related Metabolic Dysfunction by Reversing Tissue NAD+ Decline". Cell Metabolism 27 (5): 1081–1095.e10. May 2018. doi:10.1016/j.cmet.2018.03.016. PMID 29719225. 
  50. ↑ 50.0 50.1 "Location, Location, Location: Compartmentalization of NAD + Synthesis and Functions in Mammalian Cells". Trends in Biochemical Sciences 45 (10): 858–873. 2020. doi:10.1016/j.tibs.2020.05.010. PMID 32595066. PMC 7502477. https://www.jbc.org/content/294/52/19831.long. 
  51. ↑ "Implications of NAD + boosters in translational medicine". European Journal of Clinical Investigation 50 (10): e13334. 2020. doi:10.1111/eci.13334. PMID 32594513. 
  52. ↑ 52.0 52.1 52.2 "Macrophage Immunometabolism and Inflammaging: Roles of Mitochondrial Dysfunction, Cellular Senescence, CD38, and NAD". Immunometabolism 2 (3): e200026. 2020. doi:10.20900/immunometab20200026. PMID 32774895. 
  53. ↑ "Macrophages in age-related chronic inflammatory diseases". npj Aging and Mechanisms of Disease 2: 16018. 2016. doi:10.1038/npjamd.2016.18. PMID 28721272. 
  54. ↑ "Senescent cells promote tissue NAD + decline during ageing via the activation of CD38 + macrophages". Nature Metabolism 2 (11): 1265–1283. November 16, 2020. doi:10.1038/s42255-020-00305-3. PMID 33199924. 

Further reading

External links



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