The Journal of Experimental Medicine
Cytokines Montreal 2008
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Published online 26 April 2004 doi:10.1084/jem.20040373
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 199, Number 9, 1235-1244
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Somatic Hypermutation Is Limited by CRM1-dependent Nuclear Export of Activation-induced Deaminase

Kevin M. McBride1, Vasco Barreto1, Almudena R. Ramiro1, Pete Stavropoulos1, and Michel C. Nussenzweig1,2

1 Laboratory of Molecular Immunology and 2 Howard Hughes Medical Institute, The Rockefeller University, New York, NY 10021

Address correspondence to Michel C. Nussenzweig, Howard Hughes Medical Institute, The Rockefeller University, New York, NY 10021. Phone: (212) 327-8067; Fax: (212) 327-8370; email: nussen{at}mail.rockefeller.edu

Somatic hypermutation (SHM) and class switch recombination (CSR) are initiated in activated B lymphocytes by activation-induced deaminase (AID). AID is thought to make lesions in DNA by deaminating cytidine residues in single-stranded DNA exposed by RNA polymerase during transcription. Although this must occur in the nucleus, AID is found primarily in the cytoplasm. Here we show that AID is actively excluded from the nucleus by an exportin CRM1-dependent pathway. The AID nuclear export signal (NES) is found at the carboxyl terminus of AID in a region that overlaps a sequence required for CSR but not SHM. We find that AID lacking a functional NES causes more hypermutation of a nonphysiologic target gene in transfected fibroblasts. However, the NES does not impact on the rate of mutation of immunoglobulin genes in B lymphocytes, suggesting that the AID NES does not limit AID activity in these cells.

Key Words: somatic hypermutation • activation-induced deaminase • nucleo-cytoplasmic trasnport • B lymphocytes • Ig class switching

Abbreviations used in this paper: AID, activation-induced deaminase; CSR, class switch recombination; GFP, green fluorescent protein; Kan, kanamycin; LMB, leptomycin B; NES, nuclear export signal; NLS, nuclear localization signal; PK, pyruvate kinase; SHM, somatic hypermutation; ssDNA, single-stranded DNA.


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