%0 Journal Article %T Regulation of activation-induced deaminase stability and antibody gene diversification by Hsp90. %+ Institut de Recherches Cliniques de Montréal (IRCM) %+ Department of Microbiology and Immunology, Faculty of Medicine %+ Centre de Recherche Hôpital Maisonneuve-Rosemont %+ Institut Armand Frappier (INRS-IAF) %+ Department of Biochemistry [Montréal] %+ Department of Medicine, Faculty of Medicine %+ Division of Experimental Medicine, Department of Medicine %A Orthwein, Alexandre %A Patenaude, Anne-Marie %A Affar, El Bachir %A Lamarre, Alain %A Young, Jason C %A Di Noia, Javier M %Z This work was funded by grants from The Cancer Research Society andCanadian Institutes of Health Research (CIHR; MOP-84543) and supported by aCanadian Foundation for Innovation Leaders Opportunity Fund equipment grant to J.M. Di Noia. A. Orthwein was supported in part by a Michel Bélanger fellowship from the Institut de Recherches Cliniques de Montréal, by an Excellence Fellowship from the Department of Microbiology and Immunology, University of Montréal, and by a Cole Foundation Fellowship. A. Lamarre is supported by the Jeanne and J.-Louis Lévesque Chair in Immunovirology of the J.-Louis Lévesque Foundation and by CIHR. J.M. Di Noia and J.C. Young are supported by Canada Research Chairs Tier 2. %< avec comité de lecture %@ 0022-1007 %J Journal of Experimental Medicine %I Rockefeller University Press %V 207 %N 12 %P 2751-65 %8 2010-11-22 %D 2010 %R 10.1084/jem.20101321 %M 21041454 %Z Life Sciences [q-bio]/Human health and pathology/Infectious diseasesJournal articles %X 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. %G English %L pasteur-00819549 %U https://riip.hal.science/pasteur-00819549 %~ RIIP %~ INRS-IAF