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类卡皮库亚-共济失调蛋白1复合物调节Notch驱动的边缘区B细胞发育和脓毒症进展。

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

作者信息

Park Jong Seok, Kang Minjung, Kim Han Bit, Hong Hyebeen, Lee Jongeun, Song Youngkwon, Hur Yunjung, Kim Soeun, Kim Tae-Kyung, Lee Yoontae

机构信息

Department of Life Sciences, Pohang University of Science and Technology (POSTECH), Pohang, Gyeongbuk, Republic of Korea.

Institute for Convergence Research and Education in Advanced Technology, Yonsei University, Seoul, Republic of Korea.

出版信息

Nat Commun. 2024 Dec 4;15(1):10579. doi: 10.1038/s41467-024-54803-z.

DOI:10.1038/s41467-024-54803-z
PMID:39632849
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11618371/
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.

摘要

滤泡性B（FOB）细胞和边缘区B（MZB）细胞在针对病原体感染的体液免疫反应中起关键作用。MZB细胞可通过分泌白细胞介素-6加重内毒素休克。在此我们表明，转录抑制因子卡皮库亚（CIC）及其结合伴侣共济失调蛋白1样（ATXN1L）在FOB和MZB细胞发育中发挥重要作用。CIC缺陷会减小FOB和MZB细胞群体的规模，而ATXN1L缺陷则特异性影响MZB细胞。B细胞受体信号传导仅在Cic缺陷的FOB细胞中受损，而Notch信号传导在Cic缺陷和Atxn1l缺陷的MZB细胞中均被破坏。从机制上讲，ETV4去抑制导致Notch1和Notch2转录受到抑制，从而抑制B细胞特异性Cic缺陷（Cic;Cd19-Cre）和Atxn1l缺陷（Atxn1l;Cd19-Cre）小鼠中的MZB细胞发育。在Cic;Cd19-Cre和Atxn1l;Cd19-Cre小鼠中，体液免疫反应和脂多糖诱导的败血症进展减弱，但在Etv4缺失后恢复。这些发现突出了CIC-ATXN1L复合物在MZB细胞发育中的重要性，并可能为败血症的治疗靶点提供原理证明。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9bd7/11618371/ff709d21ef74/41467_2024_54803_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9bd7/11618371/ce98cdeaf788/41467_2024_54803_Fig1_HTML.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9bd7/11618371/f5d821507616/41467_2024_54803_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9bd7/11618371/cf34729b4e53/41467_2024_54803_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9bd7/11618371/9a4812081108/41467_2024_54803_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9bd7/11618371/5ed3c1f1418c/41467_2024_54803_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9bd7/11618371/ff709d21ef74/41467_2024_54803_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9bd7/11618371/ce98cdeaf788/41467_2024_54803_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9bd7/11618371/32fcc55cba42/41467_2024_54803_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9bd7/11618371/a25c8f9340b7/41467_2024_54803_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9bd7/11618371/f5d821507616/41467_2024_54803_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9bd7/11618371/cf34729b4e53/41467_2024_54803_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9bd7/11618371/9a4812081108/41467_2024_54803_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9bd7/11618371/5ed3c1f1418c/41467_2024_54803_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9bd7/11618371/ff709d21ef74/41467_2024_54803_Fig8_HTML.jpg

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