AID Phosphorylation Regulates Mismatch Repair-Dependent Class Switch Recombination and Affinity Maturation

Area of Science:

• Immunology
• Molecular Biology
• Genetics

Background:

• Activation-induced cytidine deaminase (AID) initiates DNA modifications in immunoglobulin genes, essential for antibody diversification.
• The base excision repair (BER) and mismatch repair (MMR) pathways play complementary roles in class switch recombination (CSR).
• Phosphorylation of AID at serine 38 was previously suggested to regulate BER during CSR.

Purpose of the Study:

• To investigate the role of AID phosphorylation at serine 38 in CSR and somatic hypermutation (SHM).
• To elucidate the interplay between AID phosphorylation, BER, and MMR pathways in B cell antibody diversification.

Main Methods:

• Analysis of CSR and SHM in AID-deficient (AID null) mouse B cells.
• Assessment of mutation frequency in the 5'Sμ region and JH4 intron.
• Evaluation of NP-specific affinity maturation in response to NP-CGG immunization.

Main Results:

• AID-deficient B cells exhibited a complete block in CSR and negligible SHM.
• CSR and affinity maturation were impaired in AID-deficient B cells despite significant mutations in 5'Sμ and JH4 intron.
• A novel role for AID serine 38 phosphorylation in MMR-dependent CSR and affinity maturation was identified.

Conclusions:

• Phosphorylation of AID at serine 38 is essential for functional CSR and affinity maturation.
• This phosphorylation event is critical for the mismatch repair pathway's role in CSR.
• These findings uncover a previously unrecognized mechanism regulating B cell antibody diversification.