Ebola Virus Activates IRE1 alpha-Dependent XBP1u Splicing

Ebola (EBOV) and Marburg virus (MARV) are highly pathogenic filoviruses that influence cellular signaling according to their own needs. MARV has been shown to regulate the IRE1 alpha-dependent unfolded protein response (UPR) to ensure optimal virus replication. It was not known whether EBOV affects this signaling cascade, which can be beneficial or detrimental for viruses. Activation of IRE1 alpha leads to the expression of the transcription factor XBP1s, which binds to cis-acting UPR elements (UPRE), resulting in the expression of genes aimed at restoring homeostasis in the endoplasmic reticulum. We observed that EBOV infection, in contrast to MARV infection, led to UPR activation by IRE1 alpha-dependent but not ATF6-dependent signaling. We showed an activation of IRE1 alpha, XBP1s and UPRE target genes upon EBOV infection. ATF6, another UPRE transcription factor, was not activated. UPRE activation was mainly attributed to the EBOV nucleoprotein NP and the soluble glycoprotein sGP. Finally, activation of UPR by thapsigargin, a potent ER-stress inducer, in parallel to infection as well as knock-out of XBP1 had no effect on EBOV growth, while MARV proliferation was affected by thapsigargin-dependent UPR activation. Taken together EBOV and MARV differ in their strategy of balancing IRE1 alpha-dependent signaling for their own needs.