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

Guideng Li, Egest J. Pone, Daniel C. Tran, Pina J. Patel, Lisa Dao, Zhenming Xu, Paolo Casali

Research output: Contribution to journalArticle

9 Scopus citations

Abstract

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 (Fe 2+, ferrous) suppressed CSR, leading to decreased number of switched B cells, decreased postrecombination Iμ-C H 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 I H-S-C H transcription. Fe 2+ 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 Fe 2+ was specific, as shown by lack of inhibition of AID-mediated dC deamination by other bivalent metal ions, such as Zn 2+, Mn 2+, Mg 2+, or Ni 2+, and the inability of Fe 2+ 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.

Original languageEnglish (US)
Pages (from-to)21520-21529
Number of pages10
JournalJournal of Biological Chemistry
Volume287
Issue number25
DOIs
StatePublished - Jun 15 2012
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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