of the DENV NS2B3 protease complex. We demonstrate that the proteolytic activity of this viral factor is crucial for the cleavage and degradation of STING and this phenomenon impairs the production of type I IFN in DENV infected cells. Furthermore, we show that DENV NS2B3 is not able to cleave the mouse version of STING. Using STING double knockout mouse embryonic fibroblast (MEFs) and human dendritic cells, we demonstrate the relevant role of this host factor in the restriction of DENV replication in mouse cells. This is the first report showing STING as a target for cleavage and degradation by a viral protein to inhibit innate immune responses and as a host restriction factor for virus infection in primary cells.