Dataset Information

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 (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.

SUBMITTER: Xu Z

PROVIDER: S-EPMC3645988 | biostudies-literature | 2010 Sep

REPOSITORIES: biostudies-literature

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

Xu Zhenming Z 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

Nature structural & molecular biology 20100822 9

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 underg ...[more]

PMID: 20729863

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Project description:Inflammation and tissue damage in systemic lupus erythematosus (SLE) are mediated by class-switched autoantibodies reactive with nucleic acids, nucleic acid-binding proteins, phospholipids and other self-antigens. While some healthy individuals produce IgM antibodies with specificities similar to those of lupus patients, immunoglobulin class switching to mature downstream isotypes appears to be required for the generation of pathogenic autoantibodies. To characterize the cellular and molecular basis of pathogenic autoantibody production in SLE, we studied the capacity of peripheral blood B cells of naive phenotype from patients with SLE, rheumatoid arthritis (RA) or healthy control subjects to spontaneously switch to IgG and IgA. In addition, we determined the DNA sequences of the upstream evolutionary conserved sequence (ECS)-Igamma promoter regulatory regions that control germline IH-CH transcription and class switch DNA recombination (CSR) to IgG1, IgG2 and IgG4. IgM+IgD+ B cells from patients with SLE, but not those from RA or healthy control subjects, underwent spontaneous CSR, as assessed by expression of germline Igamma1-Cgamma1, Igamma2-Cgamma2, Igamma3-Cgamma3, Igamma4-Cgamma4 and Ialpha1-Calpha1 transcripts, mature (switched) VHDJH-Cgamma1, VHDJH-Cgamma2, VHDJH-Cgamma3 and VHDJH-Calpha1 transcripts and secreted IgG and IgA. Although polymorphic DNA sequences were identified in the ECS-Igamma1, ECS-Igamma2 and ECS-Igamma4 promoter regions, the transcription factor-binding sites that mediate germline Igamma-Cgamma transcription were conserved in patients and controls. However, distinct patterns of nuclear protein binding to an ECS-Igamma promoter sequence that contains both positive and negative regulatory elements were observed in SLE patients and controls. These results support a role for exogenous signals, such as through CD40 ligation, rather than altered genomic sequence, in the increased production of class switched autoantibodies in SLE.

Dataset Information

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

Publications

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

Similar Datasets

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