Rift Valley fever virus virulence factor NSs targets ATF4- and XBP1-driven unfolded protein response

Both viruses activated all three ER stress sensors including PERK and IRE1. However, only MP-12 inhibited the PERK and IRE1 pathways by inhibiting the expression of their respective downstream mediators ATF4 and XBP1. ATF4 expression was inhibited at the transcriptional level, whereas XBP1 expression was inhibited at the post transcriptional level.

ATF4 depletion negatively impacted virus titer and the production of non-plaque-forming particles, resulting in alteration of the particle-to-PFU ratio of the viruses. We also showed that activation of the PERK pathway plays a pro-survival role in NSs-mut virus-infected cells, suggesting the involvement of PERK pathway in RVFV-induced cytotoxicity. Taken together, our study revealed that RVFV NSs inhibits two out of the three UPR pathways and promotes RVFV-induced cytotoxicity by inhibiting PERK pathway.