The capicua-ataxin-1-like complex regulates Notch-driven marginal zone B cell development and sepsis progression

Jong Seok Park, Minjung Kang, Han Bit Kim, Hyebeen Hong, Jongeun Lee, Youngkwon Song, Yunjung Hur, Soeun Kim, Tae-Kyung Kim and Yoontae Lee ()
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Jong Seok Park: Pohang University of Science and Technology (POSTECH)
Minjung Kang: Pohang University of Science and Technology (POSTECH)
Han Bit Kim: Pohang University of Science and Technology (POSTECH)
Hyebeen Hong: Pohang University of Science and Technology (POSTECH)
Jongeun Lee: Pohang University of Science and Technology (POSTECH)
Youngkwon Song: Pohang University of Science and Technology (POSTECH)
Yunjung Hur: Pohang University of Science and Technology (POSTECH)
Soeun Kim: Pohang University of Science and Technology (POSTECH)
Tae-Kyung Kim: Pohang University of Science and Technology (POSTECH)
Yoontae Lee: Pohang University of Science and Technology (POSTECH)

Nature Communications, 2024, vol. 15, issue 1, 1-15

Abstract: Abstract Follicular B (FOB) and marginal zone B (MZB) cells are pivotal in humoral immune responses against pathogenic infections. MZB cells can exacerbate endotoxic shock via interleukin-6 secretion. Here we show that the transcriptional repressor capicua (CIC) and its binding partner, ataxin-1-like (ATXN1L), play important roles in FOB and MZB cell development. CIC deficiency reduces the size of both FOB and MZB cell populations, whereas ATXN1L deficiency specifically affects MZB cells. B cell receptor signaling is impaired only in Cic-deficient FOB cells, whereas Notch signaling is disrupted in both Cic-deficient and Atxn1l-deficient MZB cells. Mechanistically, ETV4 de-repression leads to inhibition of Notch1 and Notch2 transcription, thereby inhibiting MZB cell development in B cell-specific Cic-deficient (Cicf/f;Cd19-Cre) and Atxn1l-deficient (Atxn1lf/f;Cd19-Cre) mice. In Cicf/f;Cd19-Cre and Atxn1lf/f; Cd19-Cre mice, humoral immune responses and lipopolysaccharide-induced sepsis progression are attenuated but are restored upon Etv4-deletion. These findings highlight the importance of the CIC-ATXN1L complex in MZB cell development and may provide proof of principle for therapeutic targeting in sepsis.

Date: 2024
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DOI: 10.1038/s41467-024-54803-z

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