title: Up-regulation of activating transcription factor-5 suppresses SAP expression to activate T cells in hemophagocytic syndrome associated with Epstein-Barr virus infection and immune disorders.
abstract: Hemophagocytic syndrome (HPS) is a fatal, pro-inflammatory cytokine disorder that is associated with viral infections and immune disorders. Previously, we demonstrated that Epstein-Barr virus latent membrane protein-1 (LMP-1) could down-regulate the SAP gene, enhancing Th1 cytokine secretion in T cells and leading to HPS. The exact mechanism of SAP gene regulation by LMP-1 remains to be clarified. In this study, using cDNA microarray analysis, we identified ATF5 as the candidate transcriptional repressor for SAP expression in LMP-1-expressing T cells. LMP-1 up-regulated ATF5 via TRAF2,5/NF-kappaB signals to suppress SAP gene expression. Reporter assays and electrophoretic mobility shift assays revealed that ATF5 bound differentially to two sites of the SAP promoter. In resting T cells, ATF5 bound predominantly to the high-affinity site in the -81 to -74 region while additionally binding to the low-affinity site at -305 to -296 in LMP-1-expressing T cells. Such binding subsequently disrupted the transcription of the SAP gene. At the same time, Th1 cytokine secretion was enhanced. This phenomenon was also observed in conditions such as ATF5 overexpression, phytohemagglutinin stimulation of primary T cells, and ligand engagement of T-cell lines. Therefore, the down-regulation of the SAP gene by ATF5 may represent a common mechanism for the pathogenesis of HPS that is associated with either Epstein-Barr virus infection or immune disorders with dysregulated T-cell activation.
authors.affiliation: Division of Clinical Research, National Health Research Institutes, Tainan, Taiwan.
authors.forename: Huai-Chia
authors.initials: HC
authors.lastname: Chuang
authors.forename: Ju-Ming
authors.initials: JM
authors.lastname: Wang
authors.forename: Wen-Chuan
authors.initials: WC
authors.lastname: Hsieh
authors.forename: Yao
authors.initials: Y
authors.lastname: Chang
authors.forename: Ih-Jen
authors.initials: IJ
authors.lastname: Su
mesh_terms: D051700:Activating Transcription Factor 3 / Q000378:metabolism; D051696:Activating Transcription Factors / Q000235:genetics*; D002460:Cell Line; D016207:Cytokines / Q000378:metabolism; D015536:Down-Regulation; D020031:Epstein-Barr Virus Infections / Q000150:complications* / Q000276:immunology; D006801:Humans; D007154:Immune System Diseases / Q000150:complications* / Q000276:immunology; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D008213:Lymphocyte Activation / Q000276:immunology*; D051359:Lymphohistiocytosis, Hemophagocytic / Q000150:complications / Q000235:genetics / Q000276:immunology*; D016328:NF-kappa B / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D012097:Repressor Proteins / Q000378:metabolism; D015398:Signal Transduction; D000071179:Signaling Lymphocytic Activation Molecule Associated Protein; D013601:T-Lymphocytes / Q000276:immunology; D047992:TNF Receptor-Associated Factor 2 / Q000378:metabolism; D014158:Transcription, Genetic; D015854:Up-Regulation / Q000235:genetics*; D014763:Viral Matrix Proteins / Q000378:metabolism
chemical_list: C490449:ATF3 protein, human; C507532:ATF5 protein, human; D051700:Activating Transcription Factor 3; D051696:Activating Transcription Factors; D016207:Cytokines; C037662:EBV-associated membrane antigen, Epstein-Barr virus; D047908:Intracellular Signaling Peptides and Proteins; D016328:NF-kappa B; D012097:Repressor Proteins; C114953:SH2D1A protein, human; D000071179:Signaling Lymphocytic Activation Molecule Associated Protein; D047992:TNF Receptor-Associated Factor 2; D014763:Viral Matrix Proteins