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Dhx33 promotes B-cell growth and proliferation by controlling activation-induced rRNA upregulation

Cellular & Molecular Immunology volume 20, pages 277–291 (2023)Cite this article

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Abstract

Upon recognition of foreign antigens, naïve B cells undergo rapid activation, growth, and proliferation. How B-cell growth and proliferation are coupled with activation remains poorly understood. Combining CRISPR/Cas9-mediated functional analysis and mouse genetics approaches, we found that Dhx33, an activation-induced RNA helicase, plays a critical role in coupling B-cell activation with growth and proliferation. Mutant mice with B-cell-specific deletion of Dhx33 exhibited impaired B-cell development, germinal center reactions, plasma cell differentiation, and antibody production. Dhx33-deficient B cells appeared normal in the steady state and early stage of activation but were retarded in growth and proliferation. Mechanistically, Dhx33 played an indispensable role in activation-induced upregulation of ribosomal DNA (rDNA) transcription. In the absence of Dhx33, activated B cells were compromised in their ability to ramp up 47S ribosomal RNA (rRNA) production and ribosome biogenesis, resulting in nucleolar stress, p53 accumulation, and cellular death. Our findings demonstrate an essential role for Dhx33 in coupling B-cell activation with growth and proliferation and suggest that Dhx33 inhibition is a potential therapy for lymphoma and antibody-mediated autoimmune diseases.

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Data availability

The RNA-seq data generated in this study have been deposited in the NCBI Sequence Read Archive (SRA) under accession number PRJNA850669.

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Acknowledgements

We thank all members of the CX, W-HL, and Kairui Mao labs (Xiamen University) for technical assistance. This study was supported by the National Natural Science Foundation of China (31570882, 31770950 and 32070877 to W.-H. L, and 81961138008 to CX), the Fundamental Research Funds for the Central Universities of China-Xiamen University (20720170064 to CX), and the Sanofi Institute for Biomedical Research (SIBR).

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Author notes

  1. Hyun Yong Jin

    Present address: Genentech Inc., South San Francisco, CA, 94080, USA

  2. Changchun Xiao

    Present address: Sanofi Institute for Biomedical Research, Suzhou, Jiangsu, 215123, China

  3. These authors contributed equally: Xiaoyu He, Jiayi Zhao.

Authors and Affiliations

  1. State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, Fujian, China

    Xiaoyu He, Jiayi Zhao, Abidan Adilijiang, Peicheng Hong, Pengda Chen, Xinyong Lin, Jun Xie, Ying Du, Yun Liu, Lianghua Lin, Yazhen Hong, Wen-Hsien Liu & Changchun Xiao

  2. Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA, 92037, USA

    Hyun Yong Jin & Changchun Xiao

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Contributions

CX, HYJ, and PC conceived this project. XH and JZ designed and performed most of the experiments, analyzed data, and generated figures; AA and PH performed some experiments and provided technical assistance; XL performed RNA sequencing analysis; PC, JX, YD, YL, and LL contributed to the experiments; CX and W-HL supervised the project. XH, JZ, W-HL, and CX wrote the manuscript with contributions from all authors.

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Correspondence to Wen-Hsien Liu or Changchun Xiao.

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He, X., Zhao, J., Adilijiang, A. et al. Dhx33 promotes B-cell growth and proliferation by controlling activation-induced rRNA upregulation. Cell Mol Immunol 20, 277–291 (2023). https://doi.org/10.1038/s41423-022-00972-0

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