Table 2.
Major proteins modulated by EBV dUTPase in human primary dendritic cells* that alter brain function.
| Protein | Fold-Change† | Function | Disease/Symptom Association |
|---|---|---|---|
| ACE-1/−2 (angiotensin-converting enzyme 1 & 2) | 3.00/3.00 | Zinc metallopeptidases | Alzheimer’s disease |
| ADAMTS-15 | 330.00 | Zinc metallopeptidases | Alzheimer’s disease |
| APP | 2.00 | Amyloid precursor protein | Alzheimer’s disease |
| BACE-1 | 4.00 | β-site APP cleaving enzyme 1 or β-secretase | Alzheimer’s disease |
| Brain-derived neurotrophic factor (BDNF) | 2.00 | Supports differentiation, maturation and survival of neurons and synaptic transmission | Alzheimer’s disease Depression Schizophrenia |
| Chemoattractant receptor-homologous molecule expressed on TH2 cells (CRTH2; GPR44) | 3.00 | Receptor for prostaglandin D2 | Sickness behavior |
| COX-2 | 13.00 | Cyclooxygenase 2 | Inflammation |
| Dickkopf3 (DKK3) | 3.00 | Acts as a repressor/activator of WNT/β-catenin signaling | Alzheimer’s disease |
| EN-RAGE (S100A12) | 3.00 | Ligand for RAGE; pro-inflammatory | Alzheimer's disease |
| EphB4/A1/A2/B6 (erythropoietin-producing hepatoma receptors) | 45.00/3.00/3.00/3.00 | Receptor tyrosine kinases; neural stem cell differentiation | |
| Fetulin A | 3.00 | Pro- and anti-inflammatory | Multiple sclerosis |
| Frizzled 5 | 35.00 | Receptor for WNT ligands, establishment of neuronal polarity | Alzheimer's disease |
| Galanin | 3.00 | Neuropeptide | Nociception; Alzheimer’s disease, epilepsy |
| Growth/differentiation factor 15 (GDF-15) | 5.00 | Neurotrophic factor | Oral cavity cancer |
| Glypican-5 | 8.00 | Unknown; reported to regulate WNT andhedgehog pathways | B-cell lymphoma |
| IDE (insulin degrading enzyme) | 2.74 | Amyloid-β degradation | Alzheimer’s disease |
| ITM2B | 3.00 | Regulator role in processing amyloid-β A4 | Alzheimer's disease |
| LDLR (low-density lipoprotein receptor) | 1.37 | Expressed by adult neurons; binds ApoE | Alzheimer’s disease |
| Lin41/TRIM71 | 3.00 | E3 ubiquitin protein ligase; inhibits translation of EGR1 | |
| MMP 2 (matrix metalloproteinase) | 2.00 | Calcium-dependent zinc endopeptidase | Alzheimer’s disease |
| MMP 9 (matrix metalloproteinase) | 6.00 | Calcium-dependent zinc endopeptidase | Alzheimer’s disease |
| Netrin-4 | 4.00 | Ligand for Unc-5 homologue 5; promotes terminal branching of axons | |
| Neuritin (candidate plasticity gene 15; CPG15) | 177.00 | Neurotrophin synaptic plasticity | Depression |
| Orexin A/B | 130.00/4.00 | Neuropeptides important role in hippocampal neurogenesis spatial learning and memory | Depression, learning and memory deficiencies, inflammation |
| Presenilin 1 | 2.00 | Component of γ-secretase complex | Alzheimer’s disease |
| Presenilin 2 | 21.00 | Component of γ-secretase complex | Alzheimer's disease |
| ProSAAS | 3.00 | Precursor protein processed to yield SAAS, GAV, PEN bigLEN, littleLEN | Behaviors, including anxiety, feeding, and stress |
| RAGE | 2.00 | Receptor for advanced glycation products | Alzheimer's disease |
| THY-1 (CD90) | 4.00 | T cell activation | Tumor suppressor nasopharyngeal carcinoma; axonal regeneration |
| TIMP-1, 2, 3, 4 (tissue inhibitor of metalloproteinase) | 243.00/128.00/216.00 6.00 | Major endogenous inhibitors of metalloproteinases in tissue | |
| TMEFF1 (tomorregulin-1) | 2.00 | Addicsin-associated factor | Schizophrenia |
| WIF-1 | 13.00 | Inhibitor of WNT signaling pathway | Alzheimer’s disease |
ADAMTS-15 = ADAM metallopeptidase with thrombospondin type 1 motif 15; APP = β-amyloid precursor protein; BACE = β-secretase 1; bigLEN = synonym for PCSK1N; dUTPase = deoxyuridine triphosphate nucleotidohydrolase; EBV = Epstein-Barr virus; EGR1 = early growth response 1; EN-RAGE = extracellular newly identified receptor for advanced glycation end-products binding protein; GAV = Gill-associated virus; GPR44 = putative G protein-coupled receptor 44; ITM2B = integral membrane protein 2B; littleLEN = synonym for PCSK1N; PEN = synonym for PCSK1N; ProSAAS = synonym for PCSK1N; RAGE = receptor for advanced glycation endproducts; SAAS = synonym for PCSK1N; TH2 = T helper type 2; THY-1 = Thy-cell surface antigen; TRIM71 = tripartite motif containing 71; WIF-1 = WNT inhibitory factor 1.
Human primary dendritic cells were stimulated with EBV dUTPase protein (10 μg/mL) or vehicle for 24 h. After treatment, the levels of multiple immune proteins in the culture supernatant was measured with the Human L-1000 Antibody Array (RayBiotech), as described in Methods.
Normalized signal intensity data for each analyte in EBV dUTPase-treated cells and expressed as fold-change relative to the vehicle control. Normalized data represent values in which the background signal of negative control spots on the array has been subtracted out and normalized to the mean signal intensity of positive control spots. After normalization, any ≥ 1.5-fold increase or ≤0.65-fold decrease in signal intensity for a single analyte between dUTPase and control samples was considered a measurable and significant difference in expression, provided that both sets of signals are well above background (mean background [2]; accuracy ≈ 95%).