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

• DOI: 10.1084/jem.20200137
• Publication Date: 2020-07-16T09:54:00Z
• Authors: Verónica Delgado-...; Maria Berruezo-Ll...; Robert Altwasser; Wiebke Winkler; Devakumar Sundara...; Sandhya Balasubra...; Marieta Caganova; Robin Graf; Ali Rahjouei; Marie-Thérèse Henke; Madlen Driesner; Lisa Keller; Alessandro Prigione; Martin Janz; Altuna Akalin; Michela Di Virgilio
• Keywords: Gene Editing; Male; 0301 basic medicine; Cancer Research; B-Lymphocytes; Cell Death; Genes, Immunoglobulin; Fluorescent Antibody Technique; Cell Differentiation; Mice, Transgenic; Article; Cell Line; Mice, Inbred C57BL; Mice; 03 medical and health sciences; Gene Expression Regulation; Cardiovascular and Metabolic Diseases; CRISPR-Associated Protein 9; Animals; Female; Technology Platforms; CRISPR-Cas Systems; Function and Dysfunction of the Nervous System; Antibody Diversity

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.