14-3-3 adaptor proteins recruit AID to 5'-AGCT-3'-rich switch regions for class switch recombination.
Class switch DNA recombination (CSR) is the mechanism that diversifies the biological effector functions of antibodies. Activation-induced cytidine deaminase (AID), a key protein in CSR, targets immunoglobulin H (IgH) switch regions, which contain 5'-AGCT-3' repeats in their core. How AID is recruited to switch regions remains unclear. Here we show that 14-3-3 adaptor proteins have an important role in CSR. 14-3-3 proteins specifically bound 5'-AGCT-3' repeats, were upregulated in B cells undergoing CSR and were recruited with AID to the switch regions that are involved in CSR events (Smu-->Sgamma1, Smu-->Sgamma3 or Smu-->Salpha). Moreover, blocking 14-3-3 by difopein, 14-3-3gamma deficiency or expression of a dominant-negative 14-3-3sigma mutant impaired recruitment of AID to switch regions and decreased CSR. Finally, 14-3-3 proteins interacted directly with AID and enhanced AID-mediated in vitro DNA deamination, further emphasizing the important role of these adaptors in CSR.
Xu
Zhenming
Z
Institute for Immunology, School of Medicine and School of Biological Sciences, University of California, Irvine, California, USA.
Fulop
Zsolt
Z
Wu
Guikai
G
Pone
Egest J
EJ
Zhang
Jinsong
J
Mai
Thach
T
Thomas
Lisa M
LM
Al-Qahtani
Ahmed
A
White
Clayton A
CA
Park
Seok-Rae
SR
Steinacker
Petra
P
Li
Zenggang
Z
Yates
John
J
Herron
Bruce
B
Otto
Markus
M
Zan
Hong
H
Fu
Haian
H
Casali
Paolo
P
D048948:14-3-3 Proteins / Q000172:deficiency / Q000276:immunology / Q000378:metabolism*; D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism; D001483:Base Sequence; D002460:Cell Line; D003564:Cytidine Deaminase / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D007134:Immunoglobulin Switch Region; D051379:Mice; D011485:Protein Binding; D011995:Recombination, Genetic; D000098830:AICDA (Activation-Induced Cytidine Deaminase)
D048948:14-3-3 Proteins; D000098830:AICDA (Activation-Induced Cytidine Deaminase); D003564:Cytidine Deaminase