CD38

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CD38
Protein CD38 PDB 1yh3.png
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesCD38, ADPRC1, ADPRC 1, CD38 molecule
External IDsOMIM: 107270 MGI: 107474 HomoloGene: 1345 GeneCards: CD38
EC number2.4.99.20
Gene location (Human)
Chromosome 4 (human)
Chr.Chromosome 4 (human)[1]
Chromosome 4 (human)
Genomic location for CD38
Genomic location for CD38
Band4p15.32Start15,778,275 bp[1]
End15,853,232 bp[1]
RNA expression pattern
PBB GE CD38 205692 s at fs.png
More reference expression data
Orthologs
SpeciesHumanMouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)

NM_001775

NM_007646

RefSeq (protein)

NP_001766

NP_031672

Location (UCSC)Chr 4: 15.78 – 15.85 MbChr 5: 43.87 – 43.91 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]

Function[edit]

CD38 can function either as a receptor or as an enzyme.[10] As a receptor, CD38 can attach to CD31 on the surface of T cells, thereby activating those cells to produce a variety of cytokines.[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 can be a major regulator of NAD+ levels because 100  molecules of NAD+ is required to generate one molecule of cADPR.[13] CD38 also hydrolyzes cADPR to ADPR.[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 ectoezyme 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[edit]

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.[9]

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 diagnostic marker in chronic lymphocytic leukemia and is associated with increased disease progression.[26]

Clinical application[edit]

CD38 inhibitors may be used as therapeutics for the treatment of asthma.[27]

CD38 has been used as a prognostic marker in leukemia.[28]

Daratumumab (Darzalex) which targets CD38 has been used in treating multiple myeloma.[29][30]

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.[31] 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.

Nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN) are NAD+ precursors, but when NR or NMN are administered, CD38 can degrade these precursors before they can enter cells.[32]

Aging studies[edit]

A gradual increase in CD38 has been implicated in the decline of NAD+ with age.[33][34] Treatment of old mice with a specific CD38 inhibitor, 78c, prevents age-related NAD+ decline.[35] CD38 knockout mice have twice the levels of NAD+ and are resistant to age-associated NAD+ decline,[32] with dramatically increased NAD+ levels in major organs (liver, muscle, brain, and heart).[36] On the other hand, mice overexpressing CD38 exhibit reduced NAD+ and mitochondrial dysfuntion.[32]

Macrophages are believed to be primarily responsible for the age-related increase in CD38 expression and NAD+ decline.[37] Macrophages accumulate in visceral fat and other tissues with age, leading to chronic inflammation.[38] Secretions from senescent cells induce high levels of expression of CD38 on macrophages, which becomes the major cause of NAD+ depletion with age. [39]

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[edit]

  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. PMID 2319135.
  8. ^ Nata K, Takamura T, Karasawa T, Kumagai T, Hashioka W, Tohgo A, Yonekura H, Takasawa S, Nakamura S, Okamoto H (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. PMID 23576305. S2CID 205732787.
  10. ^ 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.
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  26. ^ Burgler S (2015). "Role of CD38 Expression in Diagnosis and Pathogenesis of Chronic Lymphocytic Leukemia and Its Potential as Therapeutic Target". Critical Reviews in Immunology. 35 (5): 417–32. doi:10.1615/CritRevImmunol.v35.i5.50. PMID 26853852.
  27. ^ 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.
  28. ^ 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.
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Further reading[edit]

External links[edit]