The Capicua-ataxin-1-like Complex Regulates Notch-driven Marginal Zone B Cell Development and Sepsis Progression

Overview

Journal Nat Commun

Specialty Biology

Date 2024 Dec 5

PMID 39632849

Authors

Jong Seok Park

Minjung Kang

Han Bit Kim

Hyebeen Hong

Jongeun Lee

Youngkwon Song

Yunjung Hur

Soeun Kim

Tae-Kyung Kim

Yoontae Lee

Affiliations

Soon will be listed here.

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 (Cic;Cd19-Cre) and Atxn1l-deficient (Atxn1l;Cd19-Cre) mice. In Cic;Cd19-Cre and Atxn1l; 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.

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