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Journal articles

Regulation of activation-induced deaminase stability and antibody gene diversification by Hsp90.

Abstract : Activation-induced deaminase (AID) is the mutator enzyme that initiates somatic hypermutation and isotype switching of the antibody genes in B lymphocytes. Undesired byproducts of AID function are oncogenic mutations. AID expression levels seem to correlate with the extent of its physiological and pathological functions. In this study, we identify AID as a novel Hsp90 (heat shock protein 90 kD) client. We find that cytoplasmic AID is in a dynamic equilibrium regulated by Hsp90. Hsp90 stabilizes cytoplasmic AID, as specific Hsp90 inhibition leads to cytoplasmic polyubiquitination and proteasomal degradation of AID. Consequently, Hsp90 inhibition results in a proportional reduction in antibody gene diversification and off-target mutation. This evolutionarily conserved regulatory mechanism determines the functional steady-state levels of AID in normal B cells and B cell lymphoma lines. Thus, Hsp90 assists AID-mediated antibody diversification by stabilizing AID. Hsp90 inhibition provides the first pharmacological means to down-regulate AID expression and activity, which could be relevant for therapy of some lymphomas and leukemias.
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Contributor : Charles M. Dozois Connect in order to contact the contributor
Submitted on : Wednesday, May 1, 2013 - 9:19:48 PM
Last modification on : Monday, July 20, 2020 - 12:33:14 PM

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Alexandre Orthwein, Anne-Marie Patenaude, El Bachir Affar, Alain Lamarre, Jason C young, et al.. Regulation of activation-induced deaminase stability and antibody gene diversification by Hsp90.. Journal of Experimental Medicine, Rockefeller University Press, 2010, 207 (12), pp.2751-65. ⟨10.1084/jem.20101321⟩. ⟨pasteur-00819549⟩



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