LFA-1-dependent HuR nuclear export and cytokine mRNA stabilization in T cell activation.
Lymphokine gene expression is a precisely regulated process in T cell-mediated immune responses. In this study we demonstrate that engagement of the beta(2) integrin LFA-1 in human peripheral T cells markedly extends the half-life of TNF-alpha, GM-CSF, and IL-3 mRNA, as well as a chimeric beta-globin mRNA reporter construct containing a strongly destabilizing class II AU-rich element from the GM-CSF mRNA 3'-untranslated region. This integrin-enhanced mRNA stability leads to augmented protein production, as determined by TNF-alpha ELISPOT assays. Furthermore, T cell stimulation by LFA-1 promotes rapid nuclear-to-cytoplasmic translocation of the mRNA-stabilizing protein HuR, which in turn is capable of binding an AU-rich element sequence in vitro. Abrogation of HuR function by use of inhibitory peptides, or marked reduction of HuR levels by RNA interference, prevents LFA-1 engagement-mediated stabilization of T cell TNF-alpha or IFN-gamma transcripts, respectively. Thus, HuR-mediated mRNA stabilization, stimulated by integrin engagement and controlled at the level of HuR nuclear export, is critically involved in T cell activation.
Wang
Jin Gene
JG
Sections of Cardiovascular Medicine and Immunobiology, Vascular Biology and Transplant Program, Boyer Center for Molecular Medicine, Yale University School of Medicine, New Haven, CT 06536, USA.
Collinge
Mark
M
Ramgolam
Vinod
V
Ayalon
Oran
O
Fan
Xinhao Cynthia
XC
Pardi
Ruggero
R
Bender
Jeffrey R
JR
D021581:Active Transport, Cell Nucleus; D000954:Antigens, Surface / Q000235:genetics / Q000378:metabolism*; D001483:Base Sequence; D018106:CD28 Antigens / Q000494:pharmacology; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism*; D002478:Cells, Cultured; D016207:Cytokines / Q000235:genetics*; D003593:Cytoplasm / Q000187:drug effects / Q000378:metabolism; D051959:ELAV Proteins; D000067780:ELAV-Like Protein 1; D006801:Humans; D008213:Lymphocyte Activation / Q000187:drug effects; D016169:Lymphocyte Function-Associated Antigen-1 / Q000378:metabolism / Q000494:pharmacology*; D008969:Molecular Sequence Data; D020871:RNA Stability; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*
D000954:Antigens, Surface; D018106:CD28 Antigens; D016207:Cytokines; D051959:ELAV Proteins; D000067780:ELAV-Like Protein 1; C098770:ELAVL1 protein, human; D016169:Lymphocyte Function-Associated Antigen-1; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D016601:RNA-Binding Proteins