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

in Cellular & molecular immunology by Xiaoyu He, Jiayi Zhao, Abidan Adilijiang, Peicheng Hong, Pengda Chen, Xinyong Lin, Jun Xie, Ying Du, Yun Liu, Lianghua Lin, Hyun Yong Jin, Yazhen Hong, Wen-Hsien Liu, Changchun Xiao

TLDR

  • The study found that a protein called Dhx33 is important for B cells to grow and divide properly. Without Dhx33, B cells can't make enough of a protein they need to grow and divide, which leads to problems like lymphoma and autoimmune diseases. The study suggests that blocking Dhx33 could be a way to treat these problems.

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.

Overview

  • The study investigates the role of Dhx33 in coupling B-cell activation with growth and proliferation. The authors used CRISPR/Cas9-mediated functional analysis and mouse genetics approaches to study the effects of Dhx33 deficiency on B-cell development, germinal center reactions, plasma cell differentiation, and antibody production. The study aims to understand the mechanisms underlying B-cell growth and proliferation and identify potential therapeutic targets for lymphoma and autoimmune diseases. The hypothesis being tested is that Dhx33 plays a critical role in coupling B-cell activation with growth and proliferation.

Comparative Analysis & Findings

  • The study found that B-cell growth and proliferation were impaired in mice with B-cell-specific deletion of Dhx33. Activated B cells were retarded in growth and proliferation, and the absence of Dhx33 compromised their ability to ramp up 47S ribosomal RNA (rRNA) production and ribosome biogenesis, resulting in nucleolar stress, p53 accumulation, and cellular death. The study identified Dhx33 as an essential component of the activation-induced upregulation of ribosomal DNA (rDNA) transcription, which is critical for B-cell growth and proliferation. The findings suggest that Dhx33 inhibition is a potential therapy for lymphoma and autoimmune diseases.

Implications and Future Directions

  • The study's findings have significant implications for the field of research and clinical practice. Dhx33 inhibition could be a potential therapy for lymphoma and autoimmune diseases, as it targets a critical component of B-cell growth and proliferation. The study identifies Dhx33 as an essential component of the activation-induced upregulation of rDNA transcription, which is critical for B-cell growth and proliferation. Future research could explore the use of Dhx33 inhibitors in the treatment of lymphoma and autoimmune diseases, as well as investigate the role of Dhx33 in other immune-related disorders. The study highlights the importance of understanding the mechanisms underlying B-cell growth and proliferation and identifying potential therapeutic targets for immune-related diseases.
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