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* State Key Laboratory of Genetic Engineering, Institute of Genetics, School of Life Sciences and
Institutes of Biomedical Sciences, Fudan University, Shanghai, China;
Departments of Pharmacology and Molecular Sciences and Neuroscience, The Johns Hopkins School of Medicine, Baltimore, MD 21205; and
Department of Lymphoma and Myeloma, Center for Cancer Immunology Research, University of Texas MD Anderson Cancer Center, Houston, TX 77030
IL-2 is one of the most important cytokines required for T cell-mediated immune responses. Costimulation of CD28 in T cells up-regulates IL-2 mRNA levels via transcription activation and mRNA stabilization. Upon T cell activation, NF90, an AU-rich element (ARE)-binding protein, translocates from the nucleus into the cytoplasm, where it binds to the ARE-containing 3' untranslated regions of IL-2 mRNA and slows down degradation of IL-2 mRNA. The translocation of NF90 is mediated through a nuclear export signal at its N terminus, but how it is triggered is still unclear. Phosphorylation of ARE-binding proteins has been reported as a signal transduction pathway to stabilize ARE-containing transcripts. In this study, we demonstrate that AKT phosphorylates NF90 on Ser647 upon CD28 costimulation. This phosphorylation is necessary for nuclear export of NF90 and IL-2 mRNA stabilization by this protein, because a mutation at Ser647 abolished both functions. We observed that treatment of cells with CD28 costimulation induced distinct increase in phosphorylation of AKT and NF90 at Ser647 concomitantly. Phosphorylation at Ser647 of NF90 up-regulated IL-2 production in response to CD28 costimulation. In vivo and in vitro data support a model in which CD28 costimulation activates AKT to phosphorylate NF90 at Ser647 and phosphorylation triggers NF90 to relocate to the cytoplasm and stabilize IL-2 mRNA.
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1 This work was supported by the National 973 Program of China (2004CB518605), 863 Projects of China (2006AA020501), the Project of the Shanghai Municipal Science and Technology Commission (03dz14086), and the National Natural Science Foundation of China (30024001).
2 Address correspondence and reprint requests to Dr. Long Yu, Institute of Genetics, Fudan University, 220 Handan Road, Shanghai 200433, China. E-mail address: longyu{at}fudan.edu.cn
3 Abbreviations used in this paper: ARE, AU-rich element; AKT-CA, constitutively active AKT; AUBP, AU-binding protein; CHO, Chinese hamster ovary; CsA, cyclosporin A; CT, threshold cycle; HA, hemagglutinin; IP, immunoprecipitation; UTR, untranslated region; TTP, tristetraprolin; BRF1, butyrate response factor; NES, nuclear export signal; GSK3β, glycogen synthase kinase 3β.
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