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

Autor:	Delgado-Benito V; Laboratory of Genome Diversification and Integrity, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany., Berruezo-Llacuna M; Laboratory of Genome Diversification and Integrity, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany., Altwasser R; Laboratory of Genome Diversification and Integrity, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany.; Bioinformatics and Omics Data Science Technology Platform, Berlin Institute of Medical Systems Biology, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany., Winkler W; Laboratory of Immune Regulation and Cancer, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany.; Laboratory of Biology of Malignant Lymphomas, Experimental and Clinical Research Center, Max Delbrück Center for Molecular Medicine in the Helmholtz Association and Charité, University Medicine, Berlin, Germany., Sundaravinayagam D; Laboratory of Genome Diversification and Integrity, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany., Balasubramanian S; Laboratory of Genome Diversification and Integrity, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany., Caganova M; Laboratory of Immune Regulation and Cancer, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany., Graf R; Laboratory of Immune Regulation and Cancer, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany., Rahjouei A; Laboratory of Genome Diversification and Integrity, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany., Henke MT; Laboratory of Mitochondria and Cell Fate Reprogramming, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany., Driesner M; Laboratory of Genome Diversification and Integrity, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany., Keller L; Laboratory of Genome Diversification and Integrity, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany., Prigione A; Laboratory of Mitochondria and Cell Fate Reprogramming, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany.; Department of General Pediatrics, Neonatology and Pediatric Cardiology, University Children's Hospital, Heinrich Heine University, Düsseldorf, Germany., Janz M; Laboratory of Biology of Malignant Lymphomas, Experimental and Clinical Research Center, Max Delbrück Center for Molecular Medicine in the Helmholtz Association and Charité, University Medicine, Berlin, Germany., Akalin A; Bioinformatics and Omics Data Science Technology Platform, Berlin Institute of Medical Systems Biology, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany., Di Virgilio M; Laboratory of Genome Diversification and Integrity, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany.; Charité-Universitätsmedizin Berlin, Berlin, Germany.
Jazyk:	angličtina
Zdroj:	The Journal of experimental medicine [J Exp Med] 2020 Oct 05; Vol. 217 (10).
DOI:	10.1084/jem.20200137
Abstrakt:	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. Competing Interests: Disclosures: The authors declare no competing interests exist. (© 2020 Delgado-Benito et al.)
Databáze:	MEDLINE
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