Act1, a negative regulator in CD40- and BAFF-mediated B cell survival

Youcun Qian, Jinzhong Qin, Grace Cui, Mayumi Naramura, E. Charles Snow, Carl F. Ware, Robert L. Fairchild, Sidne A. Omori, Robert C. Rickert, Martin Scott, Brian L. Kotzin, Xiaoxia Li

Research output: Contribution to journalArticle

119 Scopus citations

Abstract

TNF receptor (TNFR) superfamily members, CD40, and BAFFR play critical roles in B cell survival and differentiation. Genetic deficiency in a novel adaptor molecule, Act1, for CD40 and BAFF results in a dramatic increase in peripheral B cells, which culminates in lymphadenopathy and splenomegaly, hypergammaglobulinemia, and autoantibodies. While the B cell-specific Act1 knockout mice displayed a similar phenotype with less severity, the pathology of the Act1-deficient mice was mostly blocked in CD40-Act1 and BAFF-Act1 double knockout mice. CD40- and BAFF-mediated survival is significantly increased in Act1-deficent B cells, with stronger IκB phosphorylation, processing of NF-κB2 (p100/p52), and activation of JNK, ERK, and p38 pathways, indicating that Act1 negatively regulates CD40- and BAFF-mediated signaling events. These findings demonstrate that Act1 plays an important role in the homeostasis of B cells by attenuating CD40 and BAFFR signaling.

Original languageEnglish (US)
Pages (from-to)575-587
Number of pages13
JournalImmunity
Volume21
Issue number4
DOIs
StatePublished - Oct 2004

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Infectious Diseases

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    Qian, Y., Qin, J., Cui, G., Naramura, M., Snow, E. C., Ware, C. F., Fairchild, R. L., Omori, S. A., Rickert, R. C., Scott, M., Kotzin, B. L., & Li, X. (2004). Act1, a negative regulator in CD40- and BAFF-mediated B cell survival. Immunity, 21(4), 575-587. https://doi.org/10.1016/j.immuni.2004.09.001