| Summary: | DDX41 is an intracellular DNA sensor that evokes type I interferon (IFN-I) production via the adaptor stimulator of interferon gene (STING), triggering innate immune responses against viral infection. However, the regulatory mechanism of the DDX41-STING pathway in teleost fish remains unclear. The mandarin fish (<i>Siniperca chuatsi</i>) is a cultured freshwater fish species that is popular in China because of its high market value. With the development of a high-density cultural mode in mandarin fish, viral diseases have increased and seriously restricted the development of aquaculture, such as ranavirus and rhabdovirus. Herein, the role of mandarin fish DDX41 (<i>sc</i>DDX41) and its DEAD and HELIC domains in the antiviral innate immune response were investigated. The level of <i>sc</i>DDX41 expression was up-regulated following treatment with poly(dA:dT) or Mandarin fish ranavirus (MRV), suggesting that <i>sc</i>DDX41 might be involved in fish innate immunity. The overexpression of <i>sc</i>DDX41 significantly increased the expression levels of IFN-I, ISGs, and pro-inflammatory cytokine genes. Co-immunoprecipitation and pull-down assays showed that the DEAD domain of <i>sc</i>DDX41 recognized the IFN stimulatory DNA and interacted with STING to activate IFN-I signaling pathway. Interestingly, the HELIC domain of <i>sc</i>DDX41 could directly interact with the N-terminal of STING to induce the expression levels of <i>IFN-I</i> and <i>ISGs</i> genes. Furthermore, the <i>sc</i>DDX41 could enhance the <i>sc</i>STING-induced IFN-I immune response and significantly inhibit MRV replication. Our work would be beneficial to understand the roles of teleost fish DDX41 in the antiviral innate immune response.
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