RNA-binding protein PTENα blocks RIG-I activation to prevent viral inflammation

doi:10.1038/s41589-024-01621-5

. 2024 May 21.

doi: 10.1038/s41589-024-01621-5. Online ahead of print.

RNA-binding protein PTENα blocks RIG-I activation to prevent viral inflammation

Yue Yin^#¹, Zeliang Yang^#¹, Yizhe Sun^#^{2

3}, Ying Yang⁴, Xin Zhang¹, Xuyang Zhao¹, Wenyu Tian¹, Yaruo Qiu¹, Yuxin Yin⁵, Fuping You⁶, Dan Lu⁷

Affiliations

¹ Institute of Systems Biomedicine, Department of Immunology, Department of Pathology, School of Basic Medical Sciences, NHC Key Laboratory of Medical Immunology, Beijing Key Laboratory of Tumor Systems Biology, Peking University Health Science Center, Beijing, P.R. China.
² Division of Infectious Diseases, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.
³ Department of Microbiology, Harvard Medical School, Boston, MA, USA.
⁴ Department of Blood Transfusion, Peking University People's Hospital, Beijing, P.R. China.
⁵ Institute of Systems Biomedicine, Department of Immunology, Department of Pathology, School of Basic Medical Sciences, NHC Key Laboratory of Medical Immunology, Beijing Key Laboratory of Tumor Systems Biology, Peking University Health Science Center, Beijing, P.R. China. yinyuxin@pku.edu.cn.
⁶ Institute of Systems Biomedicine, Department of Immunology, Department of Pathology, School of Basic Medical Sciences, NHC Key Laboratory of Medical Immunology, Beijing Key Laboratory of Tumor Systems Biology, Peking University Health Science Center, Beijing, P.R. China. fupingyou@pku.edu.cn.
⁷ Institute of Systems Biomedicine, Department of Immunology, Department of Pathology, School of Basic Medical Sciences, NHC Key Laboratory of Medical Immunology, Beijing Key Laboratory of Tumor Systems Biology, Peking University Health Science Center, Beijing, P.R. China. taotao@bjmu.edu.cn.

^# Contributed equally.

PMID: 38773328
DOI: 10.1038/s41589-024-01621-5

RNA-binding protein PTENα blocks RIG-I activation to prevent viral inflammation

Yue Yin et al. Nat Chem Biol. 2024.

. 2024 May 21.

doi: 10.1038/s41589-024-01621-5. Online ahead of print.

Authors

Yue Yin^#¹, Zeliang Yang^#¹, Yizhe Sun^#^{2

3}, Ying Yang⁴, Xin Zhang¹, Xuyang Zhao¹, Wenyu Tian¹, Yaruo Qiu¹, Yuxin Yin⁵, Fuping You⁶, Dan Lu⁷

Affiliations

¹ Institute of Systems Biomedicine, Department of Immunology, Department of Pathology, School of Basic Medical Sciences, NHC Key Laboratory of Medical Immunology, Beijing Key Laboratory of Tumor Systems Biology, Peking University Health Science Center, Beijing, P.R. China.
² Division of Infectious Diseases, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.
³ Department of Microbiology, Harvard Medical School, Boston, MA, USA.
⁴ Department of Blood Transfusion, Peking University People's Hospital, Beijing, P.R. China.
⁵ Institute of Systems Biomedicine, Department of Immunology, Department of Pathology, School of Basic Medical Sciences, NHC Key Laboratory of Medical Immunology, Beijing Key Laboratory of Tumor Systems Biology, Peking University Health Science Center, Beijing, P.R. China. yinyuxin@pku.edu.cn.
⁶ Institute of Systems Biomedicine, Department of Immunology, Department of Pathology, School of Basic Medical Sciences, NHC Key Laboratory of Medical Immunology, Beijing Key Laboratory of Tumor Systems Biology, Peking University Health Science Center, Beijing, P.R. China. fupingyou@pku.edu.cn.
⁷ Institute of Systems Biomedicine, Department of Immunology, Department of Pathology, School of Basic Medical Sciences, NHC Key Laboratory of Medical Immunology, Beijing Key Laboratory of Tumor Systems Biology, Peking University Health Science Center, Beijing, P.R. China. taotao@bjmu.edu.cn.

^# Contributed equally.

PMID: 38773328
DOI: 10.1038/s41589-024-01621-5

Abstract

A timely inflammatory response is crucial for early viral defense, but uncontrolled inflammation harms the host. Retinoic acid-inducible gene I (RIG-I) has a pivotal role in detecting RNA viruses, yet the regulatory mechanisms governing its sensitivity remain elusive. Here we identify PTENα, an N-terminally extended form of PTEN, as an RNA-binding protein with a preference for the CAUC(G/U)UCAU motif. Using both in vivo and in vitro viral infection assays, we demonstrated that PTENα restricted the host innate immune response, relying on its RNA-binding capacity and phosphatase activity. Mechanistically, PTENα directly bound to viral RNA and enzymatically converted its 5'-triphosphate to 5'-monophosphate, thereby reducing RIG-I sensitivity. Physiologically, brain-intrinsic PTENα exerted protective effects against viral inflammation, while peripheral PTENα restricted host antiviral immunity and, to some extent, promoted viral replication. Collectively, our findings underscore the significance of PTENα in modulating viral RNA- and RIG-I-mediated immune recognition, offering potential therapeutic implications for infectious diseases.

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References

1. Knight, G. M. et al. Antimicrobial resistance and COVID-19: intersections and implications. eLife 10, e64139 (2021). - PubMed - PMC - DOI
1. Gong, T., Liu, L., Jiang, W. & Zhou, R. DAMP-sensing receptors in sterile inflammation and inflammatory diseases. Nat. Rev. Immunol. 20, 95–112 (2020). - PubMed - DOI
1. Kumar, H., Kawai, T. & Akira, S. Pathogen recognition by the innate immune system. Int. Rev. Immunol. 30, 16–34 (2011). - PubMed - DOI
1. Loo, Y. M. & Gale, M. Jr. Immune signaling by RIG-I-like receptors. Immunity 34, 680–692 (2011). - PubMed - PMC - DOI
1. Iselin, L. et al. Uncovering viral RNA–host cell interactions on a proteome-wide scale. Trends Biochem. Sci. 47, 23–38 (2022). - PubMed - PMC - DOI

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82022032, 81991505, 82221003 and 82171826/National Natural Science Foundation of China (National Science Foundation of China)

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- NCI CPTC Antibody Characterization Program

[1] Knight, G. M. et al. Antimicrobial resistance and COVID-19: intersections and implications. eLife 10, e64139 (2021). - PubMed - PMC - DOI

[2] Knight, G. M. et al. Antimicrobial resistance and COVID-19: intersections and implications. eLife 10, e64139 (2021). - PubMed - PMC - DOI

[3] Gong, T., Liu, L., Jiang, W. & Zhou, R. DAMP-sensing receptors in sterile inflammation and inflammatory diseases. Nat. Rev. Immunol. 20, 95–112 (2020). - PubMed - DOI

[4] Gong, T., Liu, L., Jiang, W. & Zhou, R. DAMP-sensing receptors in sterile inflammation and inflammatory diseases. Nat. Rev. Immunol. 20, 95–112 (2020). - PubMed - DOI

[5] Kumar, H., Kawai, T. & Akira, S. Pathogen recognition by the innate immune system. Int. Rev. Immunol. 30, 16–34 (2011). - PubMed - DOI

[6] Kumar, H., Kawai, T. & Akira, S. Pathogen recognition by the innate immune system. Int. Rev. Immunol. 30, 16–34 (2011). - PubMed - DOI

[7] Loo, Y. M. & Gale, M. Jr. Immune signaling by RIG-I-like receptors. Immunity 34, 680–692 (2011). - PubMed - PMC - DOI

[8] Loo, Y. M. & Gale, M. Jr. Immune signaling by RIG-I-like receptors. Immunity 34, 680–692 (2011). - PubMed - PMC - DOI

[9] Iselin, L. et al. Uncovering viral RNA–host cell interactions on a proteome-wide scale. Trends Biochem. Sci. 47, 23–38 (2022). - PubMed - PMC - DOI

[10] Iselin, L. et al. Uncovering viral RNA–host cell interactions on a proteome-wide scale. Trends Biochem. Sci. 47, 23–38 (2022). - PubMed - PMC - DOI

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RNA-binding protein PTENα blocks RIG-I activation to prevent viral inflammation

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RNA-binding protein PTENα blocks RIG-I activation to prevent viral inflammation

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