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The DDB1-DCAF2 complex is essential for B cell development because it regulates cell cycle progression

Cellular & Molecular Immunology volume 18, pages 758–760 (2021)Cite this article

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B cell development in the bone marrow is critical for producing numerous B cells that play an essential role in the adaptive immune response. B cells develop from common lymphoid progenitors (CLPs), which then differentiate through a series of stages, which include prepro-B cells, pro-B cells, pre-B cells, immature B cells, and mature B cells.1 Within the pro-B stage, cells undergo proliferation to expand the pro-B cell pool and complete the recombination of the VH to DHJH segments to form the μ chain. However, the mechanisms involved in pro-B cell development are not fully understood. There have been several studies about the critical role of ubiquitination modifications in B cell development.2,3 Here, we report that DNA damage binding protein 1 (DDB1), an adaptor protein in CUL4-ring E3 ligases that is highly expressed in a variety of highly proliferative precursor cells,4 is involved in regulating pro-B cell development.

Within the pro-B stage, IL-7 signaling provides survival and proliferation signaling and regulates the V-DJ recombination of immunoglobulin heavy chain.5 However, DDB1 deletion did not induce obvious defects in IL-7R expression in pro-B cells (Fig. S2a). During the pro-B stage, only cells with successfully rearranged V-DJ segments enter the next stage. PAX5 is an important regulator of VH-DHJH recombination. DDB1 deletion did not affect PAX5 expression in pro-B cells (Fig. S2b). The recombination of DH to JH and proximal VH segments (VH7183 and VHQ52 to DHJH) was intact, while the recombination of distal VH segments (VHGam3.8, VH3609, and VHJ558 to DHJH) was slightly diminished in DDB1-deficient pro-B cells (Fig. S2c). This finding might explain the modest decrease in the intracellular μ chain in DDB1-deficient pro-B cells (Fig. S2d). It was unclear whether the loss of pro-B cells was resulted from elevated apoptosis. We performed Annexin V staining and found that the percentage of Annexin V-positive pro-B cells was comparable between wild-type and DDB1-deficient mice (Fig. S2e). Therefore, the severe loss of pro-B cells in DDB1-deficient mice was not caused by altered IL-7R expression, V-DJ recombination of IgH or cell apoptosis.

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Acknowledgements

We thank Dr. Xiaolong Liu (Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences) for his generous gifts of cell lines and plasmids. We thank Yingying Huang, Yanwei Li, and Jiajia Wang (Core Facilities, School of Medicine, Zhejiang University) for helping with cell sorting; Yu Zhang and Huihui Jin (Laboraty Animal Center, Zhejiang University) for feeding the mice; Xuliang Zhang, Yanxia Ding (Laboraty Animal Center, Zhejiang University), Xiaoyu Meng, and Xiaoqian Liu (Institute of Immunology, Zhejiang University School of Medicine) for the animal study; and Wenqiang Cao and Zhaoyuan hui (Institute of Immunology, Zhejiang University School of Medicine) for improving the writing. This work was supported in part by grants from the National Natural Science Foundation of China (81830006, 31670887, 31870874, and 31800734), Zhejiang Provincial Key Project of Research and Development (2019C03043), Zhejiang Natural Science Foundation (LQ16H030003), and Zhejiang Science and Technology Program (2017C37117 and 2017C37170).

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  1. These authors contributed equally: Zhonghui Xue, Jing Guo

Authors and Affiliations

  1. Bone Marrow Transplantation Center of the First Affiliated Hospital, and Institute of Immunology, Zhejiang University School of Medicine, Hangzhou, China

    Zhonghui Xue, Jing Guo, Ruoyu Ma, Lina Zhou, Yixin Guo & Lie Wang

  2. Institute of Hematology, Zhejiang University and Zhejiang Engineering Laboratory for Stem Cell and Immunotherapy, Hangzhou, China

    Zhonghui Xue, Jing Guo, Ruoyu Ma, Lina Zhou, Yixin Guo, Wenbin Qian & Lie Wang

  3. Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, Nantong, Jiangsu, China

    Zhonghui Xue

  4. School of Life Science and Technology, ShanghaiTech University, Shanghai, China

    Yong Cang

  5. MOE Key Laboratory for Biosystems Homeostasis and Protection and Innovation Center for Cell Signaling Network, Life Sciences Institute, Zhejiang University, Hangzhou, China

    Hengyu Fan

  6. Department of General Surgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China

    Jian Chen

  7. Laboratory Animal Center, Zhejiang University, Hangzhou, China

    Lie Wang

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Contributions

Lie Wang, Zhonghui Xue, and Jing Guo designed the study. Zhonghui Xue, Jing Guo, Ruoyu Ma, Lina Zhou, and Yixin Guo performed the experiments and data analysis. Lie Wang, Zhonghui Xue, and Jing Guo wrote the paper. Yong Cang and Hengyu Fan provided the reagents. Jian Chen and Wenbin Qian provided expertise and advice. Lie Wang supervised the project.

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Correspondence to Lie Wang.

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Xue, Z., Guo, J., Ma, R. et al. The DDB1-DCAF2 complex is essential for B cell development because it regulates cell cycle progression. Cell Mol Immunol 18, 758–760 (2021). https://doi.org/10.1038/s41423-020-0390-2

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