While this manuscript was under review, Yu and colleagues reported by overexpression experiments that the DENV protease can cleave the adaptor molecule MITA, [43] . In the present report we provide important data on the role of this adaptor molecule in primary human and mouse cells and during the context of DENV infection. We also confirmed the cleavage and degradation of STING by the DENV NS2B3 protease in human MDDCs in the context of DENV infection, since it is important to validate these findings in a relevant primary cell system and during virus infection ( Figure 1H ). In primary human cells as well as in mouse cells, such as MEFs and DCs, we also found that the presence of human STING allowed for greater DENV replication and the presence of mouse STING seemed to restrict DENV replication (Figure 3, figure 4 and figure 7) . We also show that the NS2B3 protease of DENV has specificity for the human STING and not for the mouse homologue of this protein ( Figure 5 and figure 6 ), suggesting that STING may be an important restriction factor in mice. Several viral proteases have been described as proteins that modulate cellular pathways, allowing many viruses to modify the intra and extracellular environment to promote optimal conditions for replication and spread. Some of the most remarkable characteristics observed at early times after infection by DENV are the lack of IFNa/b induction and a robust induction of proinflammatory cytokines like TNFa [24, 25] . As it was described in our previous work, DENV infection can abrogate IRF3 phosphorylation, but has no impact on NF-kB activity [25] . Using recombinant viruses expressing DENV-NS2B3 we observed a clear effect on the induction of TNFa in human DCs, similar to that observed with DENV infection (Figure 3 and figure 8) . Also, the inhibition of luciferase activity driven by p55-C1B promoter was considerably more efficient when compared with IFNbpromoter, since p55-C1B only harbors sites for IRF3/7 transcription factors, and IFNb-Luc has also has response elements for NFkb and AP-1 transcription factors (Figures 2B and 2D ). Furthermore, Ishikawa et al. overexpressed STING in 293T cells in the presence of different promoters driving the luciferase gene. Interestingly, STING stimulated IFNb promoter up to 400-fold, IRF3 response element (PRDIII-I-Luc) up to 1,000-fold, and NFkb responsive promoter (NF-kb-Luc) only up to 12-fold [41] . This observation suggested that STING is fundamentally involved in phosphorylation of IRF3, and under these experimental conditions showed a 100 fold less influence on NF-kb induction. Taken together, these observations suggest that DENV NS2B3 protease inhibits IFNb production by cleavage of the adaptor STING without modifying the observed NF-kb activity induced after infection by DENV. Further work exploring the impact that DENV-NS2B3 has on the induction of NF-kb activity in infected cells would confirm a putative role of this viral factor in the modulation of innate immune response by the induction of proinflammatory cytokines, a hallmark phenomenon observed during infection by DENV [44] .