Nuclear export of NF90 to stabilize IL-2 mRNA is mediated by AKT-dependent phosphorylation at Ser647 in response to CD28 costimulation.
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.
Pei
Yuan
Y
State Key Laboratory of Genetic Engineering, Institute of Genetics, School of Life Sciences, Fudan University, Shanghai, China.
Zhu
Ping
P
Dang
Yongjun
Y
Wu
Jiaxue
J
Yang
Xianmei
X
Wan
Bo
B
Liu
Jun O
JO
Yi
Qing
Q
Yu
Long
L
D021581:Active Transport, Cell Nucleus; D018106:CD28 Antigens / Q000378:metabolism*; D002460:Cell Line; D002467:Cell Nucleus / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D007376:Interleukin-2 / Q000235:genetics* / Q000378:metabolism; D050779:Nuclear Factor 90 Proteins / Q000032:analysis / Q000378:metabolism*; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000032:analysis / Q000378:metabolism*; D020871:RNA Stability; D012333:RNA, Messenger / Q000378:metabolism*; D012694:Serine / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology
D018106:CD28 Antigens; C429643:ILF3 protein, human; D007376:Interleukin-2; D050779:Nuclear Factor 90 Proteins; D012333:RNA, Messenger; D012694:Serine; D051057:Proto-Oncogene Proteins c-akt