PKA-mediated phosphorylation regulates the function of activation-induced deaminase (AID) in B cells.
During humoral immune responses, two distinct genetic modification events diversify the Ig genes in germinal center (GC) B cells: somatic hypermutation and class switch recombination (CSR). Both processes require the activity of activation-induced cytidine deaminase (AID), an enzyme expressed specifically in GC B cells. However, the mechanisms that regulate AID activity are largely unknown. Here we report that protein kinase A (PKA) phosphorylates AID and regulates its activity in GC B cells. AID physically interacts with the PKA holoenzyme in the cytoplasm and is phosphorylated by the PKA catalytic subunit at specific residues. AID phosphorylation is required for CSR, because substitution of the two phosphorylation targets impairs its ability to rescue CSR in AID-deficient B cells. Pharmacologic inhibition of PKA prevents isotype class switching in a murine B-cell lymphoma cell line; conversely, B cells from mice where PKA activity is made constitutive by conditional deletion of the PKA regulatory subunit gene display enhanced CSR. These findings implicate PKA in the regulation of AID function and suggest that the control of T cell-dependent immune responses may be modulated, via AID, by signals that activate PKA.
Pasqualucci
Laura
L
Institute for Cancer Genetics and the Herbert Irving Comprehensive Cancer Center and Department of Microbiology, Columbia University, 1150 Saint Nicholas Avenue, New York, NY 10032, USA. lp171@columbia.edu
Kitaura
Yasuyuki
Y
Gu
Hua
H
Dalla-Favera
Riccardo
R
D000595:Amino Acid Sequence; D000818:Animals; D001402:B-Lymphocytes / Q000201:enzymology* / Q000378:metabolism; D002460:Cell Line; D017124:Conserved Sequence; D017868:Cyclic AMP-Dependent Protein Kinases / Q000235:genetics / Q000378:metabolism*; D003564:Cytidine Deaminase; D003593:Cytoplasm / Q000201:enzymology; D043525:Cytosine Deaminase / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D004789:Enzyme Activation; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D010766:Phosphorylation; D011485:Protein Binding; D016415:Sequence Alignment; D000098830:AICDA (Activation-Induced Cytidine Deaminase)
D017868:Cyclic AMP-Dependent Protein Kinases; D000098830:AICDA (Activation-Induced Cytidine Deaminase); D043525:Cytosine Deaminase; D003564:Cytidine Deaminase