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PDGFA-associated protein 1 protects mature B lymphocytes from stress-induced cell death and promotes antibody gene

Verónica Delgado-Benito1, Maria Berruezo-Llacuna1, Robert Altwasser1,2

  • 1Laboratory of Genome Diversification and Integrity, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany.

The Journal of Experimental Medicine
|July 2, 2020
PubMed

The establishment of protective humoral immunity is dependent on the ability of mature B cells to undergo antibody gene diversification while adjusting to the physiological stressors induced by activation with the antigen. Mature B cells diversify their antibody genes by class switch recombination (CSR) and somatic hypermutation (SHM), which are both dependent on efficient induction of activation-induced cytidine deaminase (AID). Here, we identified PDGFA-associated protein 1 (Pdap1) as an essential regulator of cellular homeostasis in mature B cells. Pdap1 deficiency leads to sustained expression of the integrated stress response (ISR) effector activating transcription factor 4 (Atf4) and induction of the ISR transcriptional program, increased cell death, and defective AID expression. As a consequence, loss of Pdap1 reduces germinal center B cell formation and impairs CSR and SHM. Thus, Pdap1 protects mature B cells against chronic ISR activation and ensures efficient antibody diversification by promoting their survival and optimal function.

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