Rack1 regulates B-cell development and function by binding to and stabilizing the transcription factor Pax5

Rack1 regulates B-cell development and function by binding to and stabilizing the transcription factor Pax5

The transcription factor Pax5 activates genes essential for B-cell development and function. However, the regulation of Pax5 expression remains elusive. The adaptor Rack1 can interact with multiple transcription factors and modulate their activation and/or stability. However, its role in the transcr...

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Published in:Cellular & molecular immunology Vol. 21; no. 11; pp. 1282 - 1295
Main Authors: Zhang, Xueting, Ma, Chenke, Lu, Yuchen, Wang, Jing, Yun, Hongfang, Jiang, Hui, Wu, Mengyao, Feng, Xiaoyao, Gai, Wenbin, Xu, Guanglei, Deng, Hongbin, Feng, Jiannan, Liu, Wanli, Shi, Taoxing, Cheng, Qianqian, Zhang, Jiyan
Format: Journal Article
Language:English
Published: London Nature Publishing Group UK 01-11-2024
Nature Publishing Group
Subjects:
631/250/1619/40
692/4028/67/1990
Adaptor proteins
Antibodies
Biomedical and Life Sciences
Biomedicine
CD19 antigen
Cell activation
Chimeras
Developmental stages
Ectopic expression
Gene regulation
Homeostasis
Immunology
Lymphocytes B
Medical Microbiology
Microbiology
Pax5 protein
Protein deficiency
Transcription activation
Transcription factors
Ubiquitination
Vaccine
B-cell development
Ubiquitination
Rack1
Pax5
BCR signaling
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Summary:The transcription factor Pax5 activates genes essential for B-cell development and function. However, the regulation of Pax5 expression remains elusive. The adaptor Rack1 can interact with multiple transcription factors and modulate their activation and/or stability. However, its role in the transcriptional control of B-cell fates is largely unknown. Here, we show that CD19-driven Rack1 deficiency leads to pro-B accumulation and a simultaneous reduction in B cells at later developmental stages. The generation of bone marrow chimeras indicates a cell-intrinsic role of Rack1 in B-cell homeostasis. Moreover, Rack1 augments BCR and TLR signaling in mature B cells. On the basis of the aberrant expression of Pax5-regulated genes, including CD19, upon Rack1 deficiency, further exploration revealed that Rack1 maintains the protein level of Pax5 through direct interaction and consequently prevents Pax5 ubiquitination. Accordingly, Mb1-driven Rack1 deficiency almost completely blocks B-cell development at the pro-B-cell stage. Ectopic expression of Pax5 in Rack1-deficient pro-B cells partially rescues B-cell development. Thus, Rack1 regulates B-cell development and function through, at least partially, binding to and stabilizing Pax5.
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ISSN:2042-0226
1672-7681
2042-0226
DOI:10.1038/s41423-024-01213-2