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The capicua-ataxin-1-like complex regulates Notch-driven marginal zone B cell development and sepsis progression.
Jong Seok Park1, Minjung Kang1, Han Bit Kim1
1Department of Life Sciences, Pohang University of Science and Technology (POSTECH), Pohang, Gyeongbuk, Republic of Korea.
Nature Communications
|December 5, 2024
Summary
The capicua (CIC)-ataxin-1-like (ATXN1L) complex is crucial for follicular B (FOB) and marginal zone B (MZB) cell development. Targeting this complex may offer a therapeutic strategy for sepsis.
Area of Science:
- Immunology
- Molecular Biology
- Cell Biology
Background:
- Follicular B (FOB) and marginal zone B (MZB) cells are critical for adaptive immunity.
- MZB cells contribute to endotoxic shock severity through interleukin-6 secretion.
- The transcriptional repressor capicua (CIC) and its partner ataxin-1-like (ATXN1L) roles in B cell subsets are not fully understood.
Purpose of the Study:
- To investigate the role of the CIC-ATXN1L complex in FOB and MZB cell development and function.
- To elucidate the molecular mechanisms underlying the impact of CIC and ATXN1L on B cell subsets.
- To evaluate the therapeutic potential of targeting the CIC-ATXN1L pathway in sepsis models.
Main Methods:
- Generation of B cell-specific Cic-deficient (Cicf/f;Cd19-Cre) and Atxn1l-deficient (Atxn1lf/f;Cd19-Cre) mouse models.
- Analysis of FOB and MZB cell populations, B cell receptor, and Notch signaling pathways.
- Assessment of humoral immune responses and lipopolysaccharide-induced sepsis progression.
Main Results:
- CIC deficiency reduced both FOB and MZB cell populations, while ATXN1L deficiency specifically impacted MZB cells.
- CIC deficiency impaired B cell receptor signaling in FOB cells; Notch signaling was disrupted in both Cic- and Atxn1l-deficient MZB cells.
- ETV4 de-repression inhibited Notch1/Notch2 transcription, hindering MZB cell development. Humoral immunity and sepsis were attenuated in deficient mice but restored upon Etv4 deletion.
Conclusions:
- The CIC-ATXN1L complex is essential for FOB and MZB cell development.
- The CIC-ATXN1L complex regulates MZB cell development via ETV4-mediated inhibition of Notch signaling.
- Targeting the CIC-ATXN1L complex presents a potential therapeutic strategy for sepsis.
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