RT Journal Article SR Electronic T1 Pdap1 protects mature B lymphocytes from stress-induced cell death and promotes antibody gene diversification JF bioRxiv FD Cold Spring Harbor Laboratory SP 2020.01.30.917062 DO 10.1101/2020.01.30.917062 A1 VerĂ³nica Delgado-Benito A1 Maria Berruezo-Llacuna A1 Robert Altwasser A1 Wiebke Winkler A1 Sandhya Balasubramanian A1 Devakumar Sundaravinayagam A1 Robin Graf A1 Ali Rahjouei A1 Madlen Driesner A1 Lisa Keller A1 Martin Janz A1 Altuna Akalin A1 Michela Di Virgilio YR 2020 UL http://biorxiv.org/content/early/2020/01/31/2020.01.30.917062.abstract AB 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.