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Regulated localization of an AID complex with E2A, PAX5 and IRF4 at the Igh locus
Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
2016 (English)In: Molecular Immunology, ISSN 0161-5890, E-ISSN 1872-9142, Vol. 80, 78-90 p.Article in journal (Refereed) Published
Abstract [en]

Activation-induced cytidine deaminase (AID) is the key mutagenic enzyme that initiates somatic hypermutation (SH) and class switch recombination (CSR) by deaminating cytosine to uracil. The targeting of AID and therefore SH and CSR to Ig genes is a central process of the immune system, but the trans-acting factors mediating the specific targeting have remained elusive. Here we show that defective calmodulin inhibition of the transcription factor E2A after activation of the B cell receptor (BCR) leads to reduced BCR, IL4 plus CD40 ligand stimulated CSR to IgE and instead CSR to other Ig classes. AID that initiates CSR is shown to be in a complex with the transcription factors E2A, PAX5 and IRF4 on key sequences of the Igh locus. Calmodulin shows proximity with each of them after BCR stimulation. BCR signaling reduces binding of the proteins to some of the target sites on the Igh locus, and calmodulin resistance of E2A blocks these reductions. AID binds directly to the bHLH domain of E2A and to the PD domain of PAX5. E2A, AID, PAX5 and IRF4 are components of a CSR complex that is redistributed on the Igh locus by BCR signaling through calmodulin binding.

Place, publisher, year, edition, pages
2016. Vol. 80, 78-90 p.
Keyword [en]
Class switch recombination, Antibodies, Activation-induced cytidine deaminase, Transcription factors, E2A, Calmodulin
National Category
Cell and Molecular Biology
Identifiers
URN: urn:nbn:se:umu:diva-130546DOI: 10.1016/j.molimm.2016.10.014ISI: 000395847100010Scopus ID: 2-s2.0-84994651161OAI: oai:DiVA.org:umu-130546DiVA: diva2:1067772
Available from: 2017-01-23 Created: 2017-01-23 Last updated: 2017-05-15Bibliographically approved

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Hauser, JannekGrundström, ChristineKumar, RameshGrundström, Thomas
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Citation style
  • apa
  • harvard1
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  • vancouver
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