title: Optimal functional levels of activation-induced deaminase specifically require the Hsp40 DnaJa1.
abstract: The enzyme activation-induced deaminase (AID) deaminates deoxycytidine at the immunoglobulin genes, thereby initiating antibody affinity maturation and isotype class switching during immune responses. In contrast, off-target DNA damage caused by AID is oncogenic. Central to balancing immunity and cancer is AID regulation, including the mechanisms determining AID protein levels. We describe a specific functional interaction between AID and the Hsp40 DnaJa1, which provides insight into the function of both proteins. Although both major cytoplasmic type I Hsp40s, DnaJa1 and DnaJa2, are induced upon B-cell activation and interact with AID in vitro, only DnaJa1 overexpression increases AID levels and biological activity in cell lines. Conversely, DnaJa1, but not DnaJa2, depletion reduces AID levels, stability and isotype switching. In vivo, DnaJa1-deficient mice display compromised response to immunization, AID protein and isotype switching levels being reduced by half. Moreover, DnaJa1 farnesylation is required to maintain, and farnesyltransferase inhibition reduces, AID protein levels in B cells. Thus, DnaJa1 is a limiting factor that plays a non-redundant role in the functional stabilization of AID.
authors.affiliation: Laboratory of Mechanisms of Genetic Diversity, Institut de Recherches Cliniques de Montréal, Montréal, Québec, Canada.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Orthwein
authors.forename: Astrid
authors.initials: A
authors.lastname: Zahn
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Methot
authors.forename: David
authors.initials: D
authors.lastname: Godin
authors.forename: Silvestro G
authors.initials: SG
authors.lastname: Conticello
authors.forename: Kazutoyo
authors.initials: K
authors.lastname: Terada
authors.forename: Javier M
authors.initials: JM
authors.lastname: Di Noia
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D003564:Cytidine Deaminase / Q000378:metabolism*; D005260:Female; D050956:HSP40 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D000098830:AICDA (Activation-Induced Cytidine Deaminase)
chemical_list: C494639:Dnaja1 protein, mouse; D050956:HSP40 Heat-Shock Proteins; D000098830:AICDA (Activation-Induced Cytidine Deaminase); D003564:Cytidine Deaminase
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