Stability and translation of TCR zeta mRNA are regulated by the adenosine-uridine-rich elements in splice-deleted 3' untranslated region of zeta-chain.
Systemic lupus erythematosus (SLE) T cells display reduced expression of TCR zeta protein. Recently, we reported that in SLE T cells, the residual TCR zeta protein is predominantly derived from an alternatively spliced form that undergoes splice deletion of 562 nt (from 672 to 1233 bases) within the 3' untranslated region (UTR) of TCR zeta mRNA. The stability and translation of the alternatively spliced form of TCR zeta mRNA are low compared with that of the wild-type TCR zeta mRNA. We report that two adenosine-uridine-rich sequence elements (AREs), defined by the splice-deleted 3' UTR region, but not an ARE located upstream are responsible for securing TCR zeta mRNA stability and translation. The stabilizing effect of the splice-deleted region-defined AREs extended to the luciferase mRNA and was not cell type-specific. The findings demonstrate distinct sequences within the splice-deleted region 672 to 1233 of the 3' UTR, which regulate the transcription, mRNA stability, and translation of TCR zeta mRNA. The absence of these sequences represents a molecular mechanism that contributes to altered TCR zeta-chain expression in lupus.
Chowdhury
Bhabadeb
B
Department of Cellular Injury, Walter Reed Army Institute of Research, 503 Robert Grant Avenue, Silver Spring, MD 20910, USA.
Krishnan
Sandeep
S
Tsokos
Christos G
CG
Robertson
James W
JW
Fisher
Carolyn U
CU
Nambiar
Madhusoodana P
MP
Tsokos
George C
GC
D020413:3' Untranslated Regions / Q000235:genetics*; D000241:Adenosine / Q000235:genetics; D017398:Alternative Splicing; D001483:Base Sequence; D006801:Humans; D008180:Lupus Erythematosus, Systemic / Q000235:genetics*; D008565:Membrane Proteins / Q000235:genetics*; D008969:Molecular Sequence Data; D014176:Protein Biosynthesis; D020871:RNA Stability; D012333:RNA, Messenger / Q000235:genetics*; D011948:Receptors, Antigen, T-Cell / Q000235:genetics*; D014158:Transcription, Genetic; D014529:Uridine / Q000235:genetics
D020413:3' Untranslated Regions; D008565:Membrane Proteins; D012333:RNA, Messenger; D011948:Receptors, Antigen, T-Cell; C054979:antigen T cell receptor, zeta chain; D000241:Adenosine; D014529:Uridine