14-3-3 adaptor proteins recruit AID to 5 '-AGCT-3 '-rich switch regions for class switch recombination

• Authors: Zhenming Xu, University of California Irvine; Zsolt Fulop, University of California Irvine; Guika Wu, University of California Irvine; Egest J. Pone, University of California Irvine; Jinsong Zhang, University of California Irvine; Thach Mai, University of California Irvine; Lisa M. Thomas, University of California Irvine; Ahmed Al-Qahtani, University of California Irvine; Clayton A. White, University of California Irvine; Seok-Rae Park, University of California Irvine; Petra Steinacker, Ulm University; Zenggang Li, Emory University; John Yates III, The Scripps Research Institute; Bruce Herron, New York State Department of Health; Markus Otto, Ulm University; Hong Zan, University of California Irvine; Haian Fu, Emory University; Paolo Casali, University of California Irvine
• Journal Title: Nature Structural and Molecular Biology
• Volume: Volume 17, Number 9
• Publisher: Nature Research (part of Springer Nature) | 2010-09-01, Pages 1124-U13
• Type of Work: Article | Post-print: After Peer Review
• Publisher DOI: http://doi.org/10.1038/nsmb.1884
• Subjects: Biology, Cell; Biology, Molecular
• Keywords: Science & Technology; Life Sciences & Biomedicine; Biochemistry & Molecular Biology; Biophysics; Cell Biology; SINGLE-STRANDED-DNA; IMMUNOGLOBULIN GENE DIVERSIFICATION; ACTIVATION-INDUCED DEAMINASE; SOMATIC HYPERMUTATION; CYTIDINE DEAMINASE; DEPENDENT GENERATION; NUCLEAR-EXPORT; B-CELLS; EXPRESSION; IG

Abstract

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 (Sμ→Sγ1, Sμ→Sγ3 or Sμ→Sa). Moreover, blocking 14-3-3 by difopein, 14-3-3g deficiency or expression of a dominant-negative 14-3-3α 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.