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

Orthwein, Alexandre; Patenaude, Anne-Marie; Affar, El Bachir; Lamarre, Alain ORCID: https://orcid.org/0000-0002-7913-871X; Young, Jason C. et Di Noia, Javier M. (2010). Regulation of activation-induced deaminase stability and antibody gene diversification by Hsp90 Journal of Experimental Medicine , vol. 207 , nº 12. pp. 2751-2765. DOI: 10.1084/jem.20101321.

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Résumé

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.

Type de document:	Article
Mots-clés libres:	-
Centre:	Centre INRS-Institut Armand Frappier
Date de dépôt:	01 juill. 2024 02:06
Dernière modification:	01 juill. 2024 02:06
URI:	https://espace.inrs.ca/id/eprint/14998

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