Proteasomal degradation restricts the nuclear lifespan of AID.
Activation-induced cytidine deaminase (AID) initiates all postrearrangement processes that diversify the immunoglobulin repertoire by specific deamination of cytidines at the immunoglobulin (Ig) locus. As uncontrolled expression of AID is potentially mutagenic, different types of regulation, particularly nucleocytoplasmic shuttling, restrict the likelihood of AID-deoxyribonucleic acid encounters. We studied additional mechanisms of regulation affecting the stability of the AID protein. No modulation of protein accumulation according to the cell cycle was observed in a Burkitt's lymphoma cell line. In contrast, the half-life of AID was markedly reduced in the nucleus, and this destabilization was accompanied by a polyubiquitination that was revealed in the presence of proteasome inhibitors. The same compartment-specific degradation was observed in activated mouse B cells, and also in a non-B cell line. No specific lysine residues could be linked to this degradation, so it remains unclear whether polyubiquitination proceeds through several alternatives sites or through the protein N terminus. The nuclear-restricted form of AID displayed enhanced mutagenicity at both Ig and non-Ig loci, most notably at TP53, suggesting that modulation of nuclear AID content through proteasomal degradation may represent another level of control of AID activity.
Aoufouchi
Said
S
Institut National de la Santé et de la Recherche Médicale U783, Développement du Système Immunitaire, and Université Paris Descartes, Faculté de Médecine, Site Necker-Enfants Malades, 75730 Paris Cedex 15, France.
Faili
Ahmad
A
Zober
Carole
C
D'Orlando
Orietta
O
Weller
Sandra
S
Weill
Jean-Claude
JC
Reynaud
Claude-Agnès
CA
D000818:Animals; D002453:Cell Cycle; D002467:Cell Nucleus / Q000502:physiology*; D003562:Cytidine / Q000378:metabolism; D043525:Cytosine Deaminase / Q000235:genetics* / Q000378:metabolism*; D004789:Enzyme Activation; D005091:Exons; D015971:Gene Expression Regulation, Enzymologic; D017930:Genes, Reporter; D007074:Immunoglobulin G / Q000378:metabolism; D007438:Introns; D007700:Kinetics; D051379:Mice; D008822:Mice, Transgenic; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D014176:Protein Biosynthesis; D014158:Transcription, Genetic
D007074:Immunoglobulin G; D003562:Cytidine; D046988:Proteasome Endopeptidase Complex; D043525:Cytosine Deaminase