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CRISPR/Cas9 Screens Reveal Multiple Layers of B cell CD40 Regulation.

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机构： [1]Division of Infectious Diseases, Department of Medicine, Brigham and Women’s Hospital, 181 Longwood Avenue, Boston, MA 02115, USA [2]Department of Microbiology, Harvard Medical School, Boston, MA 02115, USA [3]Department of Pathology, Children’s Hospital Boston, Harvard Medical School, Boston, MA 02115, USA [4]Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA [5]Graduate Program in Virology, Division of Medical Sciences, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA 02115, USA [6]Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China [7]Biosit, Universite´ de Rennes 1, 35043 Rennes, France [8]Centre National de la Recherche Scientifique UMR 6290, Institut de Ge´ ne´ tique et De´ veloppement de Rennes, 35043 Rennes, France [9]Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA [10]Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy

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CD40 has major roles in B cell development, activation, and germinal center responses. CD40 hypoactivity causes immunodeficiency whereas its overexpression causes autoimmunity and lymphomagenesis. To systematically identify B cell autonomous CD40 regulators, we use CRISPR/Cas9 genome-scale screens in Daudi B cells stimulated by multimeric CD40 ligand. These highlight known CD40 pathway components and reveal multiple additional mechanisms regulating CD40. The nuclear ubiquitin ligase FBXO11 supports CD40 expression by targeting repressors CTBP1 and BCL6. FBXO11 knockout decreases primary B cell CD40 abundance and impairs class-switch recombination, suggesting that frequent lymphoma monoallelic FBXO11 mutations may balance BCL6 increase with CD40 loss. At the mRNA level, CELF1 controls exon splicing critical for CD40 activity, while the N6-adenosine methyltransferase WTAP negatively regulates CD40 mRNA abundance. At the protein level, ESCRT negatively regulates activated CD40 levels while the negative feedback phosphatase DUSP10 limits downstream MAPK responses. These results serve as a resource for future studies and highlight potential therapeutic targets. Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.

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出版当年[2019]版：

大类 | 1 区

生物学

小类 | 2 区细胞生物学

最新[2023]版：

大类 | 1 区

生物学

小类 | 2 区细胞生物学

第一作者：

第一作者机构： [1]Division of Infectious Diseases, Department of Medicine, Brigham and Women’s Hospital, 181 Longwood Avenue, Boston, MA 02115, USA [2]Department of Microbiology, Harvard Medical School, Boston, MA 02115, USA

通讯作者：

通讯机构： [1]Division of Infectious Diseases, Department of Medicine, Brigham and Women’s Hospital, 181 Longwood Avenue, Boston, MA 02115, USA [2]Department of Microbiology, Harvard Medical School, Boston, MA 02115, USA [4]Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA [9]Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA

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