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

Zhenming Xu; Zsolt Fulop; Guikai Wu; Egest J. Pone; Jinsong Zhang; Thach Mai; Lisa M. Thomas; Ahmed Al-Qahtani; Clayton A. White; Seok Rae Park; Petra Steinacker; Zenggang Li; John Yates; Bruce Herron; Markus Otto; Hong Zan; Haian Fu; Paolo Casali

doi:10.1038/nsmb.1884

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

Zhenming Xu, Zsolt Fulop, Guikai Wu, Egest J. Pone, Jinsong Zhang, Thach Mai, Lisa M. Thomas, Ahmed Al-Qahtani, Clayton A. White, Seok Rae Park, Petra Steinacker, Zenggang Li, John Yates, Bruce Herron, Markus Otto, Hong Zan, Haian Fu, Paolo Casali

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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.

Original language	English (US)
Pages (from-to)	1124-1135
Number of pages	12
Journal	Nature Structural and Molecular Biology
Volume	17
Issue number	9
DOIs	https://doi.org/10.1038/nsmb.1884
State	Published - Sep 2010
Externally published	Yes

ASJC Scopus subject areas

Molecular Biology
Structural Biology

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Xu, Z., Fulop, Z., Wu, G., Pone, E. J., Zhang, J., Mai, T., Thomas, L. M., Al-Qahtani, A., White, C. A., Park, S. R., Steinacker, P., Li, Z., Yates, J., Herron, B., Otto, M., Zan, H., Fu, H., & Casali, P. (2010). 14-3-3 adaptor proteins recruit AID to 5'-AGCT-3'-rich switch regions for class switch recombination. Nature Structural and Molecular Biology, 17(9), 1124-1135. https://doi.org/10.1038/nsmb.1884

Xu, Z, Fulop, Z, Wu, G, Pone, EJ, Zhang, J, Mai, T, Thomas, LM, Al-Qahtani, A, White, CA, Park, SR, Steinacker, P, Li, Z, Yates, J, Herron, B, Otto, M, Zan, H, Fu, H & Casali, P 2010, '14-3-3 adaptor proteins recruit AID to 5'-AGCT-3'-rich switch regions for class switch recombination', Nature Structural and Molecular Biology, vol. 17, no. 9, pp. 1124-1135. https://doi.org/10.1038/nsmb.1884

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

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.",

author = "Zhenming Xu and Zsolt Fulop and Guikai Wu and Pone, {Egest J.} and Jinsong Zhang and Thach Mai and Thomas, {Lisa M.} and Ahmed Al-Qahtani and White, {Clayton A.} and Park, {Seok Rae} and Petra Steinacker and Zenggang Li and John Yates and Bruce Herron and Markus Otto and Hong Zan and Haian Fu and Paolo Casali",

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doi = "10.1038/nsmb.1884",

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AU - Xu, Zhenming

AU - Fulop, Zsolt

AU - Wu, Guikai

AU - Pone, Egest J.

AU - Zhang, Jinsong

AU - Mai, Thach

AU - Thomas, Lisa M.

AU - Al-Qahtani, Ahmed

AU - White, Clayton A.

AU - Park, Seok Rae

AU - Steinacker, Petra

AU - Li, Zenggang

AU - Yates, John

AU - Herron, Bruce

AU - Otto, Markus

AU - Zan, Hong

AU - Fu, Haian

AU - Casali, Paolo

PY - 2010/9

Y1 - 2010/9

N2 - 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.

AB - 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.

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

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