Regulation of activation-induced deaminase stability and antibody gene diversification by Hsp90.
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.
Institut de Recherches Cliniques de Montréal, Montréal, Québec H2W 1R7, Canada.
Alexandre
A
Orthwein
Anne-Marie
AM
Patenaude
El Bachir
el B
Affar
Alain
A
Lamarre
Jason C
JC
Young
Javier M
JM
Di Noia
D000818:Animals; D000916:Antibody Diversity; D016227:Benzoquinones / Q000494:pharmacology; D003564:Cytidine Deaminase / Q000378:metabolism*; D004795:Enzyme Stability; D016044:Fusion Proteins, bcr-abl / Q000032:analysis; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D006367:HeLa Cells; D006801:Humans; D017578:Immunoglobulin Class Switching; D047029:Lactams, Macrocyclic / Q000494:pharmacology; D051379:Mice; D044767:Ubiquitin-Protein Ligases / Q000502:physiology; D000098830:AICDA (Activation-Induced Cytidine Deaminase)
D016227:Benzoquinones; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; C112765:tanespimycin; D044767:Ubiquitin-Protein Ligases; D016044:Fusion Proteins, bcr-abl; D000098830:AICDA (Activation-Induced Cytidine Deaminase); D003564:Cytidine Deaminase