Pdap1 protects mature B lymphocytes from stress-induced cell death and promotes antibody gene diversification

Delgado-Benito, V.; Berruezo-Llacuna, M.; Altwasser, R.; Winkler, W.; Balasubramanian, S.; Sundaravinayagam, D.; Graf, R.; Rahjouei, A.; Driesner, M.; Keller, L.; Janz, M.; Akalin, A.; Di Virgilio, M.

doi:10.1101/2020.01.30.917062

bioRxiv · 10.1101/2020.01.30.917062

Pdap1 protects mature B lymphocytes from stress-induced cell death and promotes antibody gene diversification

Delgado-Benito, V.·Berruezo-Llacuna, M.·Altwasser, R.·Winkler, W.·Balasubramanian, S.·Sundaravinayagam, D.·Graf, R.·Rahjouei, A.·Driesner, M.·Keller, L.·Janz, M.·Akalin, A.·Di Virgilio, M.

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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.

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Delgado-Benito, V., Berruezo-Llacuna, M., Altwasser, R., Winkler, W., Balasubramanian, S., Sundaravinayagam, D., Graf, R., Rahjouei, A., Driesner, M., Keller, L., Janz, M., Akalin, A., Di Virgilio, M.. 2020-01-31. Pdap1 protects mature B lymphocytes from stress-induced cell death and promotes antibody gene diversification. https://doi.org/10.1101/2020.01.30.917062

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