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The tumor suppressor PTEN has a critical role in antiviral innate immunity

Nature Immunology volume 17, pages 241249 (2016) | Download Citation

Abstract

The gene encoding PTEN is one of the most frequently mutated tumor suppressor–encoding genes in human cancer. While PTEN's function in tumor suppression is well established, its relationship to anti-microbial immunity remains unknown. Here we found a pivotal role for PTEN in the induction of type I interferon, the hallmark of antiviral innate immunity, that was independent of the pathway of the kinases PI(3)K and Akt. PTEN controlled the import of IRF3, a master transcription factor responsible for IFN-β production, into the nucleus. We further identified a PTEN-controlled negative phosphorylation site at Ser97 of IRF3 and found that release from this negative regulation via the phosphatase activity of PTEN was essential for the activation of IRF3 and its import into the nucleus. Our study identifies crosstalk between PTEN and IRF3 in tumor suppression and innate immunity.

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Acknowledgements

We thank P. Feng (University of Southern California) for Irf3−/−Irf7−/− MEFs; H. Wu (University of California, Los Angeles) for primary Pten+/+ and Pten−/− MEFs; H. Li (Wuhan University) for PtenLoxP/LoxP mice; Y. Zhu and S. Liu (Wuhan University) for plasmid encoding the IL-6 or IL-8 firefly luciferase reporter; X. Chen for help with mass spectrometry; X. Zou and S. Jin for help with statistical analysis; K. Meng and H. Zhang for technical assistance; and X. Fu and Z. Jiang for critical reading and comment on the manuscripts. Supported by the National Basic Research Program of China (2010CB911803), the National Science Foundation of China (81130083 and 31221061) and Hubei Province's Outstanding Medical Academic Leader Program (D.G.).

Author information

Affiliations

  1. State Key Laboratory of Virology and Modern Virology Research Center, College of Life Sciences, Wuhan University, Wuhan, China.

    • Shun Li
    • , Mingzhu Zhu
    • , Ruangang Pan
    • , Ting Fang
    • , Yuan-Yuan Cao
    • , Xiaolu Zhao
    • , Cao-Qi Lei
    • , Lin Guo
    • , Yu Chen
    • , Hong-Bing Shu
    •  & Deyin Guo
  2. Medical Research Institute, School of Basic Medical Sciences, Wuhan University, Wuhan, China.

    • Shuliang Chen
    •  & Deyin Guo
  3. Institute of Biotechnology, University of Helsinki, Helsinki, Finland.

    • Chun-Mei Li
    •  & Eija Jokitalo
  4. Department of Pathology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China.

    • Yuxin Yin

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Contributions

S.L. and D.G. designed the experiments and wrote the manuscript.; S.L., M.Z., R.P., T.F., Y.-Y.C. and C.-M.L. performed experimental work; S.L., M.Z., S.C., X.Z., L.G., Y.C., E.J. and D.G. analyzed the data; C.-Q.L., Y.Y. and H.-B.S. provided experimental material; and D.G. conceived of and supervised the study.

Competing interests

D.G. and S.L. are applying for a patent related to PTEN's function in antiviral immunity.

Corresponding author

Correspondence to Deyin Guo.

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DOI

https://doi.org/10.1038/ni.3311

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