C‐terminal deletion‐induced condensation sequesters AID from IgH targets in immunodeficiency.

In activated B cells, activation‐induced cytidine deaminase (AID) generates programmed DNA lesions required for antibody class switch recombination (CSR), which may also threaten genome integrity. AID dynamically shuttles between cytoplasm and nucleus, and the majority stays in the cytoplasm due to active nuclear export mediated by its C‐terminal peptide. In immunodeficient‐patient cells expressing mutant AID lacking its C‐terminus, a catalytically active AID‐delC protein accumulates in the nucleus but nevertheless fails to support CSR. To resolve this apparent paradox, we dissected the function of AID‐delC proteins in the CSR process and found that they cannot efficiently target antibody genes. We demonstrate that AID‐delC proteins form condensates both in vivo and in vitro, dependent on its N‐terminus and on a surface arginine‐rich patch. Co‐expression of AID‐delC and wild‐type AID leads to an unbalanced nuclear AID‐delC/AID ratio, with AID‐delC proteins able to trap wild‐type AID in condensates, resulting in a dominant‐negative phenotype that could contribute to immunodeficiency. The co‐condensation model of mutant and wild‐type proteins could be an alternative explanation for the dominant‐negative effect in genetic disorders. Synopsis: Immunodeficiency‐associated activation‐induced deaminase (AID) variants lacking the C‐terminus behave as dominant‐negative in antibody diversification. This study reveals co‐condensation as a basis of this dominant‐negative effect, with mutant AID proteins forming condensates and trapping wild‐type AID from its substrates. The AID C‐terminus is required for its recruitment to genomic antibody switch regionsC‐terminal‐deleted AID protein forms condensates in vitro and in vivoAID condensation causes a faulty distribution of deaminase activityC‐terminal‐deleted AID co‐condensates with wild‐type protein, resulting in the dominant‐negative effect [ABSTRACT FROM AUTHOR]