Defective production of functional 98-kDa form of Elf-1 is responsible for the decreased expression of TCR zeta-chain in patients with systemic lupus erythematosus.
Systemic lupus erythematosus (SLE), the prototypic autoimmune disease, is characterized by defective expression of TCR zeta-chain. Elf-1 (E-74-like factor) is a member of the Ets (E-26-specific) family and is crucial for the basal transcription of TCR zeta-chain in Jurkat cells. We previously demonstrated that Elf-1 exists in the cytoplasm mainly as 80-kDa form and after phosphorylation and O-glycosylation it moves to the nucleus as a 98-kDa which binds DNA. We now demonstrate that Elf-1 is crucial for the transactivation of TCR zeta-chain promoter in normal and SLE T cells. Defective expression of TCR zeta-chain in SLE T cells is associated with two distinct molecular defects in the generation of the 98-kDa DNA binding Elf-1 form. In the first, the levels of the 98-kDa form were either decreased or absent. In the second, the apparent levels of the nuclear Elf-1 form were normal but included only two of the three bands into which the nuclear Elf-1 form separated in isoelectric focusing gels. Because both the transcription and the translation processes of Elf-1 gene are normal in SLE T cells, our data demonstrate that abnormal posttranslational mechanisms of the Elf-1 protein result in defective expression of functional Elf-1, and consequently, the transcriptional defect of TCR zeta-chain in patients of SLE.
Juang
Yuang-Taung
YT
Department of Cellular Injury, Walter Reed Army Institute of Research, Silver Spring, MD 20910, USA. Yuang-Taung.Juang@NA.AMEDD.ARMY.MIL
Tenbrock
Klaus
K
Nambiar
Madhusoodana P
MP
Gourley
Mark F
MF
Tsokos
G C
GC
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000378:metabolism; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology*; D036383:Ephrin-A2 / Q000096:biosynthesis* / Q000172:deficiency / Q000378:metabolism / Q000502:physiology; D005260:Female; D005786:Gene Expression Regulation / Q000235:genetics / Q000276:immunology; D006801:Humans; D007526:Isoelectric Point; D008180:Lupus Erythematosus, Systemic / Q000235:genetics / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D008875:Middle Aged; D008970:Molecular Weight; D009687:Nuclear Proteins / Q000096:biosynthesis / Q000172:deficiency / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000276:immunology; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis / Q000172:deficiency / Q000502:physiology; D050783:Proto-Oncogene Proteins c-ets; D012333:RNA, Messenger / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D011948:Receptors, Antigen, T-Cell / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D014157:Transcription Factors / Q000096:biosynthesis / Q000172:deficiency / Q000502:physiology
D004268:DNA-Binding Proteins; D036383:Ephrin-A2; D008565:Membrane Proteins; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D050783:Proto-Oncogene Proteins c-ets; D012333:RNA, Messenger; D011948:Receptors, Antigen, T-Cell; D014157:Transcription Factors; C054979:antigen T cell receptor, zeta chain