Iron inhibits activation-induced cytidine deaminase enzymatic activity and modulates immunoglobulin class switch DNA recombination

作者：Li Guideng; Pone Egest J; Tran Daniel C; Patel Pina J; Dao Lisa; Xu Zhenming^*; Casali Paolo

来源：Journal of Biological Chemistry, 2012, 287(25).

DOI：10.1074/jbc.M112.366732

• Activation induced cytidine deaminase
• Antibody response
• B cells
• Bivalent metal ions
• DNA breaks
• DNA recombination
• Dose-dependent
• Double strands
• Endonucleases
• Enzymatic activities
• Germline
• Iron ions
• Microbial pathogens
• Neoplastic transformation
• Somatic hypermutation
• Tumoral cells
• Uracil-DNA glycosylase

Immunoglobulin (Ig) class switch DNA recombination (CSR) and somatic hypermutation (SHM) are critical for the maturation of the antibody response. Activation-induced cytidine deaminase (AID) initiates CSR and SHM by deaminating deoxycytidines (dCs) in switch (S) and V(D)J region DNA, respectively, to generate deoxyuracils (dUs). Processing of dUs by uracil DNA glycosylase (UNG) yields abasic sites, which are excised by apurinic/apyrimidinic endonucleases, eventually generating double strand DNA breaks, the obligatory intermediates of CSR. Here, we found that the bivalent iron ion (Fe2+, ferrous) suppressed CSR, leading to decreased number of switched B cells, decreased postrecombination Iμ-CH transcripts, and reduced titers of secreted class-switched IgG1, IgG3, and IgA antibodies, without alterations in critical CSR factors, such as AID, 14-3-3γ, or PTIP, or in general germline IH-S-CH transcription. Fe2+ did not affect B cell proliferation or plasmacytoid differentiation. Rather, it inhibited AID-mediated dC deamination in a dose-dependent fashion. The inhibition of intrinsic AID enzymatic activity by Fe2+ was specific, as shown by lack of inhibition of AID-mediated dC deamination by other bivalent metal ions, such as Zn2+, Mn2+, Mg2+, or Ni2+, and the inability of Fe2+ to inhibit UNG-mediated dU excision. Overall, our findings have outlined a novel role of iron in modulating a B cell differentiation process that is critical to the generation of effective antibody responses to microbial pathogens and tumoral cells. They also suggest a possible role of iron in dampening AID-dependent autoimmunity and neoplastic transformation.

• 单位
  university of california