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


  • 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 of Experimental Medicine


  • J Exp Med 217 (10): e20200137


  • 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.