PP2A dephosphorylates Elf-1 and determines the expression of CD3zeta and FcRgamma in human systemic lupus erythematosus T cells.
T cells from patients with systemic lupus erythematosus are characterized by decreased expression of CD3zeta-chain and increased expression of FcRgamma-chain, which becomes part of the CD3 complex and contributes to aberrant signaling. Elf-1 enhances the expression of CD3zeta, whereas it suppresses the expression of FcRgamma gene and lupus T cells have decreased amounts of DNA-binding 98 kDa form of Elf-1. We show that the aberrantly increased PP2A in lupus T cells dephosphorylates Elf-1 at Thr-231. Dephosphorylation results in limited expression and binding of the 98 kDa Elf-1 form to the CD3zeta and FcRgamma promoters. Suppression of the expression of the PP2A leads to increased expression of CD3zeta and decreased expression of FcRgamma genes and correction of the early signaling response. Therefore, PP2A serves as a central determinant of abnormal T cell function in human lupus and may represent an appropriate treatment target.
Juang
Yuang-Taung
YT
Division of Rheumatology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA.
Wang
Ying
Y
Jiang
Guisen
G
Peng
Hai-Bin
HB
Ergin
Sukran
S
Finnell
Michelle
M
Magilavy
Abigail
A
Kyttaris
Vasileios C
VC
Tsokos
George C
GC
D000328:Adult; D017252:CD3 Complex / Q000235:genetics*; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D008180:Lupus Erythematosus, Systemic / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D009687:Nuclear Proteins / Q000235:genetics*; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D054648:Protein Phosphatase 2 / Q000378:metabolism* / Q000502:physiology; D017452:Receptors, IgG / Q000235:genetics*; D013601:T-Lymphocytes / Q000737:chemistry* / Q000276:immunology; D014157:Transcription Factors / Q000235:genetics*
D017252:CD3 Complex; C121704:CD3 antigen, zeta chain; C512897:ELF1 protein, human; D009687:Nuclear Proteins; D017452:Receptors, IgG; D014157:Transcription Factors; D054648:Protein Phosphatase 2