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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: |
Delgado-Benito, V.  ORCID: https://orcid.org/0000-0002-0077-1935, Berruezo-Llacuna, M., Altwasser, R. ORCID: https://orcid.org/0009-0002-6216-6068, Winkler, W. ORCID: https://orcid.org/0000-0001-8807-9259, Sundaravinayagam, D. ORCID: https://orcid.org/0000-0003-0717-7530, Balasubramanian, S. ORCID: https://orcid.org/0000-0003-1830-5737, Caganova, M. ORCID: https://orcid.org/0000-0002-4576-6574, Graf, R. ORCID: https://orcid.org/0000-0002-5400-9938, Rahjouei, A. ORCID: https://orcid.org/0000-0003-3973-6333, Henke, M.T. ORCID: https://orcid.org/0000-0001-6572-1667, Driesner, M., Keller, L., Prigione, A. ORCID: https://orcid.org/0000-0001-9457-1952, Janz, M. ORCID: https://orcid.org/0000-0002-1127-0044, Akalin, A. ORCID: https://orcid.org/0000-0002-0468-0117 and Di Virgilio, M. ORCID: https://orcid.org/0000-0001-5189-0793
|
| 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 |
| ISSN: | 0022-1007 |
| Publisher: | Rockefeller University Press |
| Volume: | 217 |
| Number: | 10 |
| Page Range: | e20200137 |
| Date: | 5 October 2020 |
| Official Publication: | https://doi.org/10.1084/jem.20200137 |
| PubMed: | View item in PubMed |
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