PDGFA-associated protein 1 protects mature B lymphocytes from stress-induced cell death and promotes antibody gene diversification
Authors
- V. Delgado-Benito
- M. Berruezo-Llacuna
- R. Altwasser
- W. Winkler
- D. Sundaravinayagam
- S. Balasubramanian
- M. Caganova
- R. Graf
- A. Rahjouei
- M.T. Henke
- M. Driesner
- L. Keller
- A. Prigione
- M. Janz
- A. Akalin
- M. Di Virgilio
Journal
- Journal of Experimental Medicine
Citation
- J Exp Med 217 (10): e20200137
Abstract
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.