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

Xia Xie1, Tingting Gan2, Bing Rao1

  • 1State Key Laboratory of Molecular Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China.

The EMBO Journal
|April 26, 2022
PubMed

Insights

Mutant activation-induced cytidine deaminase (AID) proteins form nuclear condensates, trapping functional AID and impairing antibody class switch recombination (CSR), potentially explaining immunodeficiency.

Area of Science:

  • Immunology
  • Molecular Biology
  • Genetics

Background:

  • Activated B cells utilize activation-induced cytidine deaminase (AID) for antibody class switch recombination (CSR).
  • AID's nuclear-cytoplasmic shuttling and nuclear export are critical for regulating its function and preventing genome instability.
  • Mutant AID lacking its C-terminus (AID-delC) accumulates in the nucleus but fails to support CSR.

Purpose of the Study:

  • To investigate the functional consequences of AID-delC protein accumulation in the nucleus.
  • To elucidate the mechanism behind the dominant-negative effect of catalytically active AID mutants.
  • To understand the role of protein condensates in AID function and immunodeficiency.

Main Methods:

  • Analysis of AID-delC protein localization and function in B cells.
  • In vitro and in vivo studies of AID-delC condensate formation.
  • Co-expression experiments with wild-type AID and AID-delC mutants.

Main Results:

  • Catalytically active AID-delC proteins fail to efficiently target antibody genes for CSR.
  • AID-delC proteins form nuclear condensates dependent on their N-terminus and an arginine-rich patch.
  • Co-expression of AID-delC with wild-type AID creates an unbalanced nuclear ratio, trapping wild-type AID in condensates and causing a dominant-negative effect.

Conclusions:

  • Nuclear condensate formation by mutant AID proteins is a key mechanism for dominant-negative effects.
  • This co-condensation model provides an explanation for immunodeficiency observed in patients with AID mutations.
  • Targeting AID condensate formation may offer therapeutic strategies for certain genetic disorders.

Keywords:
activation-induced cytidine deaminaseclass switch recombinationdominant-negativeimmunodeficiencyprotein condensation

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