TY - JOUR
T1 - Act1, a negative regulator in CD40- and BAFF-mediated B cell survival
AU - Qian, Youcun
AU - Qin, Jinzhong
AU - Cui, Grace
AU - Naramura, Mayumi
AU - Snow, E. Charles
AU - Ware, Carl F.
AU - Fairchild, Robert L.
AU - Omori, Sidne A.
AU - Rickert, Robert C.
AU - Scott, Martin
AU - Kotzin, Brian L.
AU - Li, Xiaoxia
N1 - Funding Information:
This work was supported by National Institutes for Health Grant GM 600020 to X.L.
PY - 2004/10
Y1 - 2004/10
N2 - 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.
AB - 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.
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U2 - 10.1016/j.immuni.2004.09.001
DO - 10.1016/j.immuni.2004.09.001
M3 - Article
C2 - 15485634
AN - SCOPUS:5644271413
SN - 1074-7613
VL - 21
SP - 575
EP - 587
JO - Immunity
JF - Immunity
IS - 4
ER -
