FasL expression in activated T lymphocytes involves HuR-mediated stabilization.
A prolonged activation of the immune system is one of the main causes of hyperproliferation of lymphocytes leading to defects in immune tolerance and autoimmune diseases. Fas ligand (FasL), a member of the TNF superfamily, plays a crucial role in controlling this excessive lymphoproliferation by inducing apoptosis in T cells leading to their rapid elimination. Here, we establish that posttranscriptional regulation is part of the molecular mechanisms that modulate FasL expression, and we show that in activated T cells FasL mRNA is stable. Our sequence analysis indicates that the FasL 3'-untranslated region (UTR) contains two AU-rich elements (AREs) that are similar in sequence and structure to those present in the 3'-UTR of TNFα mRNA. Through these AREs, the FasL mRNA forms a complex with the RNA-binding protein HuR both in vitro and ex vivo. Knocking down HuR in HEK 293 cells prevented the phorbol 12-myristate 13-acetate-induced expression of a GFP reporter construct fused to the FasL 3'-UTR. Collectively, our data demonstrate that the posttranscriptional regulation of FasL mRNA by HuR represents a novel mechanism that could play a key role in the maintenance and proper functioning of the immune system.
Drury
Gillian L
GL
Department of Biochemistry, Rosalind and Morris Goodman Cancer Center, Montreal, Quebec H3G 1Y6, Canada.
Di Marco
Sergio
S
Dormoy-Raclet
Virginie
V
Desbarats
Julie
J
Gallouzi
Imed-Eddine
IE
D020413:3' Untranslated Regions; D000954:Antigens, Surface / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D017209:Apoptosis / Q000235:genetics / Q000276:immunology; D001327:Autoimmune Diseases / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D002273:Carcinogens / Q000494:pharmacology; D051959:ELAV Proteins; D000067780:ELAV-Like Protein 1; D053222:Fas Ligand Protein / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology; D005786:Gene Expression Regulation; D006801:Humans; D007108:Immune Tolerance / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D019169:Jurkat Cells; D008213:Lymphocyte Activation / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D020871:RNA Stability; D016601:RNA-Binding Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
D020413:3' Untranslated Regions; D000954:Antigens, Surface; D002273:Carcinogens; D051959:ELAV Proteins; D000067780:ELAV-Like Protein 1; C098770:ELAVL1 protein, human; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D016601:RNA-Binding Proteins; D013755:Tetradecanoylphorbol Acetate