Group 3 innate lymphoid cells (ILC3s) are important for maintaining gut homeostasis. Upon stimulation, ILC3s can rapidly produce cytokines to protect against infections and colitis. However, the regulation of ILC3 quick response is still unclear. Here, we find that eIF6 aggregates with Nsun2 and cytokine mRNA in ILC3s at steady state, which inhibits the methyltransferase activity of Nsun2 and the nuclear export of cytokine mRNA, resulting in the nuclear reservation of cytokine mRNA. Upon stimulation, phosphorylated p38α phosphorylates eIF6, which in turn releases Nsun2 activity, and promotes the nuclear export of cytokine mRNA and rapid cytokine production. Genetic disruption of p38α, Nsun2, or eIF6 in ILC3s influences the mRNA nuclear export and protein expression of the protective cytokines, thus leading to increased susceptibility to colitis. Together, our data identify a crucial role of the p38α–eIF6–Nsun2 axis in regulating rapid ILC3 immune response at the posttranscriptional level, which is critical for gut homeostasis maintenance and protection against gut inflammation.
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6 January 2025
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November 26 2024
p38α–eIF6–Nsun2 axis promotes ILC3’s rapid response to protect host from intestinal inflammation
In Special Collection:
Immunology Update Winter 2025
Jida Huang
,
Jida Huang
*
(Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Project administration, Validation, Visualization, Writing - original draft, Writing - review & editing)
1
Institute for Immunology, Tsinghua University
, Beijing, China
2
School of Basic Medical Sciences, Tsinghua University
, Beijing, China
3
Beijing Key Lab for Immunological Research on Chronic Diseases, Tsinghua University
, Beijing, China
4
State Key Laboratory of Molecular Oncology, School of Basic Medical Sciences, Tsinghua University
, Beijing, China
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Jing Zhang
,
Jing Zhang
*
(Investigation)
1
Institute for Immunology, Tsinghua University
, Beijing, China
2
School of Basic Medical Sciences, Tsinghua University
, Beijing, China
3
Beijing Key Lab for Immunological Research on Chronic Diseases, Tsinghua University
, Beijing, China
4
State Key Laboratory of Molecular Oncology, School of Basic Medical Sciences, Tsinghua University
, Beijing, China
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Panwei Song
,
Panwei Song
(Investigation)
1
Institute for Immunology, Tsinghua University
, Beijing, China
2
School of Basic Medical Sciences, Tsinghua University
, Beijing, China
3
Beijing Key Lab for Immunological Research on Chronic Diseases, Tsinghua University
, Beijing, China
4
State Key Laboratory of Molecular Oncology, School of Basic Medical Sciences, Tsinghua University
, Beijing, China
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Jiaoyan Huang
,
Jiaoyan Huang
(Investigation)
1
Institute for Immunology, Tsinghua University
, Beijing, China
2
School of Basic Medical Sciences, Tsinghua University
, Beijing, China
3
Beijing Key Lab for Immunological Research on Chronic Diseases, Tsinghua University
, Beijing, China
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Zi Yang
,
Zi Yang
(Investigation)
5
Protein Preparation and Identification Facilities at Technology Center for Protein Science, School of Life Sciences, Tsinghua University
, Beijing, China
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Jiahuai Han
,
Jiahuai Han
(Resources)
6
State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Innovation Center for Cell Signaling Network, Xiamen University
, Xiamen, China
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Li Wu
,
Li Wu
(Conceptualization, Funding acquisition, Supervision)
1
Institute for Immunology, Tsinghua University
, Beijing, China
2
School of Basic Medical Sciences, Tsinghua University
, Beijing, China
3
Beijing Key Lab for Immunological Research on Chronic Diseases, Tsinghua University
, Beijing, China
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Xiaohuan Guo
(Conceptualization, Data curation, Funding acquisition, Methodology, Project administration, Resources, Supervision, Visualization, Writing - original draft, Writing - review & editing)
1
Institute for Immunology, Tsinghua University
, Beijing, China
2
School of Basic Medical Sciences, Tsinghua University
, Beijing, China
3
Beijing Key Lab for Immunological Research on Chronic Diseases, Tsinghua University
, Beijing, China
4
State Key Laboratory of Molecular Oncology, School of Basic Medical Sciences, Tsinghua University
, Beijing, China
7
SXMU-Tsinghua Collaborative Innovation Center for Frontier Medicine, Shanxi Medical University
, Taiyuan, China
Correspondence to Xiaohuan Guo: [email protected]
Search for other works by this author on:
Jida Huang
Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Project administration, Validation, Visualization, Writing - original draft, Writing - review & editing
*
1
Institute for Immunology, Tsinghua University
, Beijing, China
2
School of Basic Medical Sciences, Tsinghua University
, Beijing, China
3
Beijing Key Lab for Immunological Research on Chronic Diseases, Tsinghua University
, Beijing, China
4
State Key Laboratory of Molecular Oncology, School of Basic Medical Sciences, Tsinghua University
, Beijing, China
1
Institute for Immunology, Tsinghua University
, Beijing, China
2
School of Basic Medical Sciences, Tsinghua University
, Beijing, China
3
Beijing Key Lab for Immunological Research on Chronic Diseases, Tsinghua University
, Beijing, China
4
State Key Laboratory of Molecular Oncology, School of Basic Medical Sciences, Tsinghua University
, Beijing, China
Panwei Song
Investigation
1
Institute for Immunology, Tsinghua University
, Beijing, China
2
School of Basic Medical Sciences, Tsinghua University
, Beijing, China
3
Beijing Key Lab for Immunological Research on Chronic Diseases, Tsinghua University
, Beijing, China
4
State Key Laboratory of Molecular Oncology, School of Basic Medical Sciences, Tsinghua University
, Beijing, China
Jiaoyan Huang
Investigation
1
Institute for Immunology, Tsinghua University
, Beijing, China
2
School of Basic Medical Sciences, Tsinghua University
, Beijing, China
3
Beijing Key Lab for Immunological Research on Chronic Diseases, Tsinghua University
, Beijing, China
Zi Yang
Investigation
5
Protein Preparation and Identification Facilities at Technology Center for Protein Science, School of Life Sciences, Tsinghua University
, Beijing, China
Jiahuai Han
Resources
6
State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Innovation Center for Cell Signaling Network, Xiamen University
, Xiamen, China
Li Wu
Conceptualization, Funding acquisition, Supervision
1
Institute for Immunology, Tsinghua University
, Beijing, China
2
School of Basic Medical Sciences, Tsinghua University
, Beijing, China
3
Beijing Key Lab for Immunological Research on Chronic Diseases, Tsinghua University
, Beijing, China
Xiaohuan Guo
Conceptualization, Data curation, Funding acquisition, Methodology, Project administration, Resources, Supervision, Visualization, Writing - original draft, Writing - review & editing
1
Institute for Immunology, Tsinghua University
, Beijing, China
2
School of Basic Medical Sciences, Tsinghua University
, Beijing, China
3
Beijing Key Lab for Immunological Research on Chronic Diseases, Tsinghua University
, Beijing, China
4
State Key Laboratory of Molecular Oncology, School of Basic Medical Sciences, Tsinghua University
, Beijing, China
7
SXMU-Tsinghua Collaborative Innovation Center for Frontier Medicine, Shanxi Medical University
, Taiyuan, China
Correspondence to Xiaohuan Guo: [email protected]
*
J. Huang and J. Zhang contributed equally to this paper.
Disclosures: The authors declare no competing interests exist.
Received:
April 08 2024
Revision Received:
September 01 2024
Accepted:
October 08 2024
Online ISSN: 1540-9538
Print ISSN: 0022-1007
Funder(s):
National Natural Science Foundation of China
- Award Id(s): 82150104,82122030,32170872,82141201,31821003,82388101,31991174
Funder(s):
National Key R&D Program of China
- Award Id(s): 2023YFC2306202,2017YFA0103602
Funder(s):
Beijing Natural Science Foundation
- Award Id(s): Z210015
Funder(s):
Ministry of Science and Technology of China
- Award Id(s): 2019YFA0508502,2020YFC2505001
Funder(s):
Shanxi Medical University
Funder(s):
Tsinghua University
© 2024 Huang et al.
2024
Huang et al.
This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/).
This work is licensed under a
Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License
.
J Exp Med (2025) 222 (1): e20240624.
Article history
Received:
April 08 2024
Revision Received:
September 01 2024
Accepted:
October 08 2024
Citation
Jida Huang, Jing Zhang, Panwei Song, Jiaoyan Huang, Zi Yang, Jiahuai Han, Li Wu, Xiaohuan Guo; p38α–eIF6–Nsun2 axis promotes ILC3’s rapid response to protect host from intestinal inflammation. J Exp Med 6 January 2025; 222 (1): e20240624. doi: https://doi.org/10.1084/jem.20240624
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