Critical role of class IA PI3K for c-Rel expression in B lymphocytes

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  • Satoshi Matsuda
    Department of Microbiology and Immunology, Keio University School of Medicine, Tokyo;
  • Yohei Mikami
    Department of Microbiology and Immunology, Keio University School of Medicine, Tokyo;
  • Masashi Ohtani
    Department of Microbiology and Immunology, Keio University School of Medicine, Tokyo;
  • Mari Fujiwara
    Department of Microbiology and Immunology, Keio University School of Medicine, Tokyo;
  • Yasuko Hirata
    Department of Microbiology and Immunology, Keio University School of Medicine, Tokyo;
  • Akiko Minowa
    Department of Microbiology and Immunology, Keio University School of Medicine, Tokyo;
  • Yasuo Terauchi
    Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Tokyo; and
  • Takashi Kadowaki
    Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Tokyo; and
  • Shigeo Koyasu
    Department of Microbiology and Immunology, Keio University School of Medicine, Tokyo;

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<jats:title>Abstract</jats:title><jats:p>The fact that the Xid mutation of Btk impairs the ability of pleckstrin homo-logy domain of Btk to bind phosphatidylinositol-(3,4,5)-trisphosphate, a product of class IA phosphoinositide-3 kinases (PI3Ks), has been considered strong evidence for the hypothesis that Btk functions downstream of PI3Ks. We demonstrate here that the Xid mutation renders the Btk protein unstable. Furthermore, class IA PI3K- and Btk-deficient mice show different phenotypes in B-cell development, collectively indicating that PI3Ks and Btk differentially function in BCR signal transduction. Nevertheless, both PI3K and Btk are required for the activation of NF-κB, a critical transcription factor family for B-cell development and function. We demonstrate that PI3Ks maintain the expression of NF-κB proteins, whereas Btk is known to be essential for IκB degradation and the translocation of NF-κB to the nucleus. The loss of PI3K activity results in marked reduction of c-Rel and to a lesser extent RelA expression. The lentivirus-mediated introduction of c-Rel corrects both developmental and proliferative defects in response to BCR stimulation in class IA PI3K-deficient B cells. These results show that the PI3K-mediated control of c-Rel expression is essential for B-cell functions.</jats:p>

Journal

  • Blood

    Blood 113 (5), 1037-1044, 2009-01-29

    American Society of Hematology

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