GADD34 DC/DC MEFs were exposed to CHIKV-GFP (MOI of 10 or 50) for 24 and 48 h. Productive infection was estimated by GFP expression and virus titration (Fig. 6A) , and culture supernatants monitored for the presence of type-I IFN (Fig. 6B , left). Only minimal CHIKV infection (15%) could be observed at maximum MOI in WT MEFs (Fig. 6A, left) , while robust IFN-b amounts were already produced at the lowest MOI (Fig. 6B) . Contrasting with WT cells and regardless of the MOI used, a higher level of viral replication was observed in GADD34 DC/DC MEFs (Fig. 6A) . The GADD34-inactivated cells were clearly more sensitive to CHIKV, displaying a 50% infection rate after 24 h of infection (MOI 50) and a log more of virus titer in culture supernatants (Fig. 6A, right) . Correlated with their susceptibility to CHIKV infection, IFN-b production was nearly undetectable in GADD34 DC/DC MEFs (Fig. 6B) . Such observation confirms the incapacity of GADD34-deficient cells to produce cytokines in response to cytosolic dsRNA, a deficiency likely to facilitate viral replication. This interpretation is further supported by the abrogation of viral replication in both WT and GADD34 DC/DC MEFs briefly treated with IFN-b (Fig. 6C) . Thus, GADD34 inactivation does not favor viral replication per se, but is critical for type-I IFN production. Interestingly infection levels were found to be higher in PKR2/2 than in GADD34 DC/DC MEFs, although this difference could be attributed to clonal MEFs variation, it more likely suggests that PKR-dependent translation arrest could be key in preventing early viral replication in this system. In addition, the relatively lower permissivity of GADD34 DC/DC MEFs to infection at high MOI could indicate the existence of GADD34-dependent defense mechanisms, which could be independent from IFN production and eIF2-a dephosphorylation. To strengthen and generalize these observations, we treated a different strain of WT MEFs with guanabenz and examined the consequences for CHIKV infection. Biochemically, GADD34 expression was induced upon CHIKV infection, and guanabenz treatment resulted in a clear increase in eIF2a phosphorylation, demonstrating the importance of GADD34 in limiting this process during infection (Fig. 6D, right) . As observed with GADD34 DC/DC cells, pharmacological and RNAi inhibition of GADD34 was found to increase significantly the sensitivity of MEFs to infection, while reducing their IFN-b production ( Fig. 6D and S10) . Thus, induction of GADD34 and its phosphatase activity during CHIKV infection, in vitro, participates to normal type-I IFN production and control of viral dissemination.