The molecular mechanism by which inborn errors of the human RNA lariat–debranching enzyme 1 (DBR1) underlie brainstem viral encephalitis is unknown. We show here that the accumulation of RNA lariats in human DBR1-deficient cells interferes with stress granule (SG) assembly, promoting the proteasome degradation of at least G3BP1 and G3BP2, two key components of SGs. In turn, impaired assembly of SGs, which normally recruit PKR, impairs PKR activation and activity against viruses, including HSV-1. Remarkably, the genetic ablation of PKR abolishes the corresponding antiviral effect of DBR1 in vitro. We also show that Dbr1Y17H/Y17H mice are susceptible to similar viral infections in vivo. Moreover, cells and brain samples from Dbr1Y17H/Y17H mice exhibit decreased G3BP1/2 expression and PKR phosphorylation. Thus, the debranching of RNA lariats by DBR1 permits G3BP1/2- and SG assembly-mediated PKR activation and cell-intrinsic antiviral immunity in mice and humans. DBR1-deficient patients are prone to viral disease because of intracellular lariat accumulation, which impairs G3BP1/2- and SG assembly-dependent PKR activation.
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6 January 2025
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December 05 2024
Human DBR1 deficiency impairs stress granule–dependent PKR antiviral immunity
Shuo Ru
,
Shuo Ru
(Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Project administration, Resources, Supervision, Validation, Visualization, Writing - original draft, Writing - review & editing)
1Division Life Sciences and Medicine, Department of General Surgery, The First Affiliated Hospital of USTC, Key Laboratory of Immune Response and Immunotherapy, Center Advanced Interdisciplinary Science and Biomedicine IHM,
University of Science and Technology of China
, Hefei, China
2Division of Life Sciences and Medicine, Institute of Immunology and the CAS Key Laboratory of Innate Immunity and Chronic Disease,
University of Science and Technology of China
, Hefei, China
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Sisi Tang
,
Sisi Tang
(Investigation, Resources, Validation)
1Division Life Sciences and Medicine, Department of General Surgery, The First Affiliated Hospital of USTC, Key Laboratory of Immune Response and Immunotherapy, Center Advanced Interdisciplinary Science and Biomedicine IHM,
University of Science and Technology of China
, Hefei, China
2Division of Life Sciences and Medicine, Institute of Immunology and the CAS Key Laboratory of Innate Immunity and Chronic Disease,
University of Science and Technology of China
, Hefei, China
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Hui Xu
,
Hui Xu
(Data curation, Formal analysis, Investigation, Methodology, Resources, Validation, Visualization)
1Division Life Sciences and Medicine, Department of General Surgery, The First Affiliated Hospital of USTC, Key Laboratory of Immune Response and Immunotherapy, Center Advanced Interdisciplinary Science and Biomedicine IHM,
University of Science and Technology of China
, Hefei, China
2Division of Life Sciences and Medicine, Institute of Immunology and the CAS Key Laboratory of Innate Immunity and Chronic Disease,
University of Science and Technology of China
, Hefei, China
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Jiahao Yin
,
Jiahao Yin
(Resources, Validation)
1Division Life Sciences and Medicine, Department of General Surgery, The First Affiliated Hospital of USTC, Key Laboratory of Immune Response and Immunotherapy, Center Advanced Interdisciplinary Science and Biomedicine IHM,
University of Science and Technology of China
, Hefei, China
2Division of Life Sciences and Medicine, Institute of Immunology and the CAS Key Laboratory of Innate Immunity and Chronic Disease,
University of Science and Technology of China
, Hefei, China
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Yan Guo
,
Yan Guo
(Formal analysis, Investigation, Resources, Writing - review & editing)
1Division Life Sciences and Medicine, Department of General Surgery, The First Affiliated Hospital of USTC, Key Laboratory of Immune Response and Immunotherapy, Center Advanced Interdisciplinary Science and Biomedicine IHM,
University of Science and Technology of China
, Hefei, China
2Division of Life Sciences and Medicine, Institute of Immunology and the CAS Key Laboratory of Innate Immunity and Chronic Disease,
University of Science and Technology of China
, Hefei, China
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Liuping Song
,
Liuping Song
(Data curation, Resources, Validation)
1Division Life Sciences and Medicine, Department of General Surgery, The First Affiliated Hospital of USTC, Key Laboratory of Immune Response and Immunotherapy, Center Advanced Interdisciplinary Science and Biomedicine IHM,
University of Science and Technology of China
, Hefei, China
2Division of Life Sciences and Medicine, Institute of Immunology and the CAS Key Laboratory of Innate Immunity and Chronic Disease,
University of Science and Technology of China
, Hefei, China
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Zhenyu Jin
,
Zhenyu Jin
(Resources, Software, Validation)
3Division of Life Science and Medicine,
The First Affiliated Hospital of USTC, University of Science and Technology of China
, Hefei, China
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Danyel Lee
,
Danyel Lee
(Writing - review & editing)
4St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch,
The Rockefeller University
, New York, NY, USA
5Laboratory of Human Genetics of Infectious Diseases,
Necker Branch, INSERM U1163
, Paris, France
6
Paris Cité University, Imagine Institute
, Paris, France
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Yi-Hao Chan
,
Yi-Hao Chan
(Formal analysis, Investigation, Methodology, Validation, Writing - review & editing)
4St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch,
The Rockefeller University
, New York, NY, USA
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Xingyao Chen
,
Xingyao Chen
(Investigation)
2Division of Life Sciences and Medicine, Institute of Immunology and the CAS Key Laboratory of Innate Immunity and Chronic Disease,
University of Science and Technology of China
, Hefei, China
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Luke Buerer
,
Luke Buerer
(Formal analysis, Software, Visualization)
7Department of Molecular Biology, Cell Biology and Biochemistry,
Brown University
, Providence, RI, USA
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William Fairbrother
,
William Fairbrother
(Conceptualization, Investigation, Writing - original draft, Writing - review & editing)
7Department of Molecular Biology, Cell Biology and Biochemistry,
Brown University
, Providence, RI, USA
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Weidong Jia
,
Weidong Jia
(Funding acquisition)
1Division Life Sciences and Medicine, Department of General Surgery, The First Affiliated Hospital of USTC, Key Laboratory of Immune Response and Immunotherapy, Center Advanced Interdisciplinary Science and Biomedicine IHM,
University of Science and Technology of China
, Hefei, China
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Jean-Laurent Casanova
,
Jean-Laurent Casanova
(Funding acquisition, Project administration, Supervision, Writing - review & editing)
4St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch,
The Rockefeller University
, New York, NY, USA
5Laboratory of Human Genetics of Infectious Diseases,
Necker Branch, INSERM U1163
, Paris, France
6
Paris Cité University, Imagine Institute
, Paris, France
8Department of Pediatrics,
Necker Hospital for Sick Children, AP-HP
, Paris, France
9
Howard Hughes Medical Institute
, New York, NY, USA
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Shen-Ying Zhang
,
Shen-Ying Zhang
(Conceptualization, Funding acquisition, Investigation, Supervision, Writing - review & editing)
4St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch,
The Rockefeller University
, New York, NY, USA
5Laboratory of Human Genetics of Infectious Diseases,
Necker Branch, INSERM U1163
, Paris, France
6
Paris Cité University, Imagine Institute
, Paris, France
Search for other works by this author on:
Daxing Gao
(Conceptualization, Data curation, Funding acquisition, Project administration, Resources, Supervision, Visualization, Writing - original draft, Writing - review & editing)
1Division Life Sciences and Medicine, Department of General Surgery, The First Affiliated Hospital of USTC, Key Laboratory of Immune Response and Immunotherapy, Center Advanced Interdisciplinary Science and Biomedicine IHM,
University of Science and Technology of China
, Hefei, China
2Division of Life Sciences and Medicine, Institute of Immunology and the CAS Key Laboratory of Innate Immunity and Chronic Disease,
University of Science and Technology of China
, Hefei, China
4St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch,
The Rockefeller University
, New York, NY, USA
Correspondence to Daxing Gao: [email protected]
Search for other works by this author on:
Shuo Ru
Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Project administration, Resources, Supervision, Validation, Visualization, Writing - original draft, Writing - review & editing
1Division Life Sciences and Medicine, Department of General Surgery, The First Affiliated Hospital of USTC, Key Laboratory of Immune Response and Immunotherapy, Center Advanced Interdisciplinary Science and Biomedicine IHM,
University of Science and Technology of China
, Hefei, China
2Division of Life Sciences and Medicine, Institute of Immunology and the CAS Key Laboratory of Innate Immunity and Chronic Disease,
University of Science and Technology of China
, Hefei, China
Sisi Tang
Investigation, Resources, Validation
1Division Life Sciences and Medicine, Department of General Surgery, The First Affiliated Hospital of USTC, Key Laboratory of Immune Response and Immunotherapy, Center Advanced Interdisciplinary Science and Biomedicine IHM,
University of Science and Technology of China
, Hefei, China
2Division of Life Sciences and Medicine, Institute of Immunology and the CAS Key Laboratory of Innate Immunity and Chronic Disease,
University of Science and Technology of China
, Hefei, China
Hui Xu
Data curation, Formal analysis, Investigation, Methodology, Resources, Validation, Visualization
1Division Life Sciences and Medicine, Department of General Surgery, The First Affiliated Hospital of USTC, Key Laboratory of Immune Response and Immunotherapy, Center Advanced Interdisciplinary Science and Biomedicine IHM,
University of Science and Technology of China
, Hefei, China
2Division of Life Sciences and Medicine, Institute of Immunology and the CAS Key Laboratory of Innate Immunity and Chronic Disease,
University of Science and Technology of China
, Hefei, China
Jiahao Yin
Resources, Validation
1Division Life Sciences and Medicine, Department of General Surgery, The First Affiliated Hospital of USTC, Key Laboratory of Immune Response and Immunotherapy, Center Advanced Interdisciplinary Science and Biomedicine IHM,
University of Science and Technology of China
, Hefei, China
2Division of Life Sciences and Medicine, Institute of Immunology and the CAS Key Laboratory of Innate Immunity and Chronic Disease,
University of Science and Technology of China
, Hefei, China
Yan Guo
Formal analysis, Investigation, Resources, Writing - review & editing
1Division Life Sciences and Medicine, Department of General Surgery, The First Affiliated Hospital of USTC, Key Laboratory of Immune Response and Immunotherapy, Center Advanced Interdisciplinary Science and Biomedicine IHM,
University of Science and Technology of China
, Hefei, China
2Division of Life Sciences and Medicine, Institute of Immunology and the CAS Key Laboratory of Innate Immunity and Chronic Disease,
University of Science and Technology of China
, Hefei, China
Liuping Song
Data curation, Resources, Validation
1Division Life Sciences and Medicine, Department of General Surgery, The First Affiliated Hospital of USTC, Key Laboratory of Immune Response and Immunotherapy, Center Advanced Interdisciplinary Science and Biomedicine IHM,
University of Science and Technology of China
, Hefei, China
2Division of Life Sciences and Medicine, Institute of Immunology and the CAS Key Laboratory of Innate Immunity and Chronic Disease,
University of Science and Technology of China
, Hefei, China
Zhenyu Jin
Resources, Software, Validation
3Division of Life Science and Medicine,
The First Affiliated Hospital of USTC, University of Science and Technology of China
, Hefei, China
Danyel Lee
Writing - review & editing
4St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch,
The Rockefeller University
, New York, NY, USA
5Laboratory of Human Genetics of Infectious Diseases,
Necker Branch, INSERM U1163
, Paris, France
6
Paris Cité University, Imagine Institute
, Paris, France
Yi-Hao Chan
Formal analysis, Investigation, Methodology, Validation, Writing - review & editing
4St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch,
The Rockefeller University
, New York, NY, USA
Xingyao Chen
Investigation
2Division of Life Sciences and Medicine, Institute of Immunology and the CAS Key Laboratory of Innate Immunity and Chronic Disease,
University of Science and Technology of China
, Hefei, China
Luke Buerer
Formal analysis, Software, Visualization
7Department of Molecular Biology, Cell Biology and Biochemistry,
Brown University
, Providence, RI, USA
William Fairbrother
Conceptualization, Investigation, Writing - original draft, Writing - review & editing
7Department of Molecular Biology, Cell Biology and Biochemistry,
Brown University
, Providence, RI, USA
Weidong Jia
Funding acquisition
1Division Life Sciences and Medicine, Department of General Surgery, The First Affiliated Hospital of USTC, Key Laboratory of Immune Response and Immunotherapy, Center Advanced Interdisciplinary Science and Biomedicine IHM,
University of Science and Technology of China
, Hefei, China
Jean-Laurent Casanova
Funding acquisition, Project administration, Supervision, Writing - review & editing
4St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch,
The Rockefeller University
, New York, NY, USA
5Laboratory of Human Genetics of Infectious Diseases,
Necker Branch, INSERM U1163
, Paris, France
6
Paris Cité University, Imagine Institute
, Paris, France
8Department of Pediatrics,
Necker Hospital for Sick Children, AP-HP
, Paris, France
9
Howard Hughes Medical Institute
, New York, NY, USA
Shen-Ying Zhang
Conceptualization, Funding acquisition, Investigation, Supervision, Writing - review & editing
4St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch,
The Rockefeller University
, New York, NY, USA
5Laboratory of Human Genetics of Infectious Diseases,
Necker Branch, INSERM U1163
, Paris, France
6
Paris Cité University, Imagine Institute
, Paris, France
Daxing Gao
Conceptualization, Data curation, Funding acquisition, Project administration, Resources, Supervision, Visualization, Writing - original draft, Writing - review & editing
1Division Life Sciences and Medicine, Department of General Surgery, The First Affiliated Hospital of USTC, Key Laboratory of Immune Response and Immunotherapy, Center Advanced Interdisciplinary Science and Biomedicine IHM,
University of Science and Technology of China
, Hefei, China
2Division of Life Sciences and Medicine, Institute of Immunology and the CAS Key Laboratory of Innate Immunity and Chronic Disease,
University of Science and Technology of China
, Hefei, China
4St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch,
The Rockefeller University
, New York, NY, USA
Correspondence to Daxing Gao: [email protected]
Disclosures: W. Fairbrother reported being a co-founder of Walah Scientific, a COVID breathalyzer company. W. Fairbrother is on the SAB of ReMIX. No other disclosures were reported.
Received:
January 02 2024
Revision Received:
June 25 2024
Accepted:
September 20 2024
Online ISSN: 1540-9538
Print ISSN: 0022-1007
Funder(s):
National Key R&D Program of China
- Award Id(s): 2023YFC2306100
Funder(s):
Chinese Academy of Sciences
- Award Id(s): XDB0490000,XDB0940302
Funder(s):
National Natural Science Foundation of China
- Award Id(s): 31970855,32270914
Funder(s):
University of Science and Technology of China
Funder(s):
National Center for Advancing Translational Sciences
Funder(s):
National Institutes of Health
- Award Id(s): R01AI088364,R01NS072381,UL1TR001866
Funder(s):
French National Research Agency
- Award Id(s): ANR-10-LABX-62-IBEID,ANR-10-IAHU-01,ANR-19-CE15-0009-01
Funder(s):
General Atlantic Foundation
Funder(s):
Rockefeller University
Funder(s):
Howard Hughes Medical Institute
Funder(s):
Institut National de la Santé et de la Recherche Médicale
Funder(s):
Imagine Institute
Funder(s):
Paris Cité University
Funder(s):
St. Giles Foundation
Funder(s):
French Medical Research Foundation
© 2024 Ru et al.
2024
Ru 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): e20240010.
Article history
Received:
January 02 2024
Revision Received:
June 25 2024
Accepted:
September 20 2024
Connected Content
Citation
Shuo Ru, Sisi Tang, Hui Xu, Jiahao Yin, Yan Guo, Liuping Song, Zhenyu Jin, Danyel Lee, Yi-Hao Chan, Xingyao Chen, Luke Buerer, William Fairbrother, Weidong Jia, Jean-Laurent Casanova, Shen-Ying Zhang, Daxing Gao; Human DBR1 deficiency impairs stress granule–dependent PKR antiviral immunity. J Exp Med 6 January 2025; 222 (1): e20240010. doi: https://doi.org/10.1084/jem.20240010
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