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

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Item Type:Article
Title:PDGFA-associated protein 1 protects mature B lymphocytes from stress-induced cell death and promotes antibody gene diversification
Creators Name:Delgado-Benito, V. and Berruezo-Llacuna, M. and Altwasser, R. and Winkler, W. and Sundaravinayagam, D. and Balasubramanian, S. and Caganova, M. and Graf, R. and Rahjouei, A. and Henke, M.T. and Driesner, M. and Keller, L. and Prigione, A. and Janz, M. and Akalin, A. and Di Virgilio, M.
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.
Keywords:Antibody Diversity, B-Lymphocytes, CRISPR-Associated Protein 9, CRISPR-Cas Systems, Cell Death, Cell Differentiation, Cell Line, Fluorescent Antibody Technique, Gene Editing, Gene Expression Regulation, Immunoglobulin Genes, Inbred C57BL Mice, Transgenic Mice, Animals, Mice
Source:Journal of Experimental Medicine
Publisher:Rockefeller University Press
Page Range:e20200137
Date:5 October 2020
Official Publication:https://doi.org/10.1084/jem.20200137
PubMed:View item in PubMed
Related to:
https://edoc.mdc-berlin.de/18786/Preprint version

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