B-cell receptor activation inhibits AID expression through calmodulin inhibition of E-proteins.
Upon encountering antigens, B-lymphocytes can adapt to produce a highly specific and potent antibody response. Somatic hypermutation, which introduces point mutations in the variable regions of antibody genes, can increase the affinity for antigen, and antibody effector functions can be altered by class switch recombination (CSR), which changes the expressed constant region exons. Activation-induced cytidine deaminase (AID) is the mutagenic antibody diversification enzyme that is essential for both somatic hypermutation and CSR. The mutagenic AID enzyme has to be tightly controlled. Here, we show that engagement of the membrane-bound antibodies of the B-cell receptor (BCR), which signals that good antibody affinity has been reached, inhibits AID gene expression and that calcium (Ca(2+)) signaling is essential for this inhibition. Moreover, we show that overexpression of the Ca(2+) sensor protein calmodulin inhibits AID gene expression, and that the transcription factor E2A is required for regulation of the AID gene by the BCR. E2A mutated in the binding site for calmodulin, and thus showing calmodulin-resistant DNA binding, makes AID expression resistant to the inhibition through BCR activation. Thus, BCR activation inhibits AID gene expression through Ca(2+)/calmodulin inhibition of E2A.
Hauser
Jannek
J
Department of Molecular Biology, Umeå University, SE-901 87 Umeå, Sweden.
Sveshnikova
Natalia
N
Wallenius
Anders
A
Baradaran
Sanna
S
Saarikettu
Juha
J
Grundström
Thomas
T
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000502:physiology; D020013:Calcium Signaling / Q000235:genetics; D002147:Calmodulin / Q000502:physiology*; D045744:Cell Line, Tumor; D003564:Cytidine Deaminase / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D020033:Protein Isoforms / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology; D012333:RNA, Messenger / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D051381:Rats; D011947:Receptors, Antigen, B-Cell / Q000378:metabolism* / Q000502:physiology; D051820:TCF Transcription Factors / Q000235:genetics / Q000378:metabolism; D058125:Transcription Factor 7-Like 1 Protein; D000098830:AICDA (Activation-Induced Cytidine Deaminase)
D051792:Basic Helix-Loop-Helix Proteins; D002147:Calmodulin; D003564:Cytidine Deaminase; D020033:Protein Isoforms; D012333:RNA, Messenger; D011947:Receptors, Antigen, B-Cell; D051820:TCF Transcription Factors; D058125:Transcription Factor 7-Like 1 Protein; D000098830:AICDA (Activation-Induced Cytidine Deaminase); C407909:TCF3 protein, human; C544912:TCF7L1 protein, human; C544913:Tcf7l1 protein, mouse