The Antiviral Function And Its Underlying Mechanisms Of The Tumor Suppressor PTEN

Detection of microbial pathogen is the first step to elicit the innate immune responses through a set of host pattern recognition receptors (PRRs) that recognize microbe-associated molecular patterns (MAMPs). For example, retinoic acid-inducible gene I (RIG-I)-like receptors (RLRs) recognize viral double-stranded RNA (dsRNA) or single-stranded RNA (ssRNA) in most cells invaded by viruses; membrane-associated toll-like receptors (TLRs) recognize viral dsRNA or ssRNA internalized into the endosomes in immune cells. Activation of PRRs triggers downstream signaling cascades that lead to rapid production of type I interferons (IFNs) and proinflammatory cytokines.Interferon-regulatory factor 3 (IRF3) acts as a master transcription factor responsible for the induction of IFN-? and is essential for the establishment of innate immunity. Upon pathogen detection, IRF3 is phosphorylated on several phosphorylation acceptor clusters and undergoes conformational change and homo-dimerization, leading to its nuclear translocation and association with the interferon-stimulated response elements (ISRE) of target genes. The essential role of IRF3 in IFN-? induction suggests that it has to be properly regulated and finely tuned to determine the exact nature of the final immune responses against invading viruses. IRF3 is phosphorylated by the upstream kinases TBKl and IKK?, but the phosphatases responsible for the dephosphorylation of IRF3 remain elusive.Phosphatase and tensin homolog deleted on chromosome ten (PTEN) is one of the most frequently mutated tumor suppressors. By antagonizing phosphoinositide 3-kinase (PI3K)-Akt signaling through its lipid phosphatase activity, PTEN governs a myriad of cellular processes and plays a central role in tumor suppression. Although its role in tumor suppression is well established, it is completely unknown whether PTEN is involved in anti-microbial immunity.Here we report a previously unknown function in antiviral immunity for PTEN. We show that PTEN plays a pivotal role in type ? interferon (IFN) induction, the hallmark of antiviral innate immunity. Our study showed that the role of PTEN in type ? IFN induction is dependent on its phosphastase activity but independent of PI3K/Akt pathway. PTEN promotes virus-induced type ? IFN production by controlling the nuclear import of interferon regulatory factor 3 (IRF3), a master transcription factor responsible for IFN-? production. PTEN is involved in all the IRF3-mediated type ? IFN production triggered by different types of viruses and nucleic acid analogs. We further identified several other phosphorylation sites that deactivate IRF3, in addition to the previously known ones that activate IRF3. Among these negative phosphorylation sites, phosphorylation of Ser97 abolishes IRF3 nuclear import, and unlashing of this negative phosphorylation regulation by PTEN phosphatase is essential for the nuclear import of IRF3 and the production of type ? IFN. Moreover, deficiency of PTEN in different cells including cancer cells leads to lowered IFN responses and increased viral infection and host cells undergoing apoptosis. We generated PTEN conditional kncokout mice and demonstrated the physilogical function of PTEN in antiviral innate immunity by revealing that PTEN conditional kncokout mice showed lowered IFN responses and highly susceptible to VSV infection. Collectively, We identified that PTEN plays a critical role in antiviral innate immunity in addition to its tumor-suppressive function; we also revealed the new mechanism underlying the negative phosphorylation regulation of IRF3 and the role of PTEN phosphatase in targeting the negative phosphorylation site on IRF3. This study unveils a crosstalk between PTEN and IRF3 in tumor suppression and innate immunity, which may in part explain why tumor cells are more susceptible to virus infection than normal cells. Overall, this study provides new insight into antiviral strategies, and also has therapeutic implications for screening and clinical treatment of PTEN-null tumors by futher application of oncolytic viruses.