• ¹State Key Laboratory of Virology and Modern Virology Research Center, College of Life Sciences, Wuhan University, Wuhan, China.
• ²Medical Research Institute, School of Basic Medical Sciences, Wuhan University, Wuhan, China.
• ³Institute of Biotechnology, University of Helsinki, Helsinki, Finland.
• ⁴Department of Pathology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China.

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 hall mark 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 aPTEN-controlled negative phosphorylation site at Ser97 of IRF3 and found that release from this negative regulation via the phosphatase activity ofPTEN 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.