Cell-cell fusion limits activation of the unfolded protein response induced by the Nipah virus glycoproteins.

The productive replication of highly pathogenic Nipah virus (NiV) relies on the host cell for the synthesis and correct folding of the viral glycoproteins, which can cause ER stress and activation of the unfolded protein response (UPR). While the UPR can exert proviral functions by restoring ER homeostasis, it can also have antiviral effects. Here, we show that irreversible ER stress induced by thapsigargin resulted in broad expression of UPR target genes and potently inhibited NiV infection. The finding that UPR target gene upregulation was not detectable in NiV-infected cells at 18 h p.i., raised the question of how NiV regulates UPR activation to prevent thapsigargin-like antiviral effects. To address this, we analyzed the effects of NiV glycoprotein expression on UPR activation and found that both NiV glycoproteins F and G, like many other viral glycoproteins, activated the highly conserved IRE1/XBP1 branch of the UPR. Interestingly, upon coexpression of both NiV glycoproteins and thereby induced cell-cell fusion, the activation did not increase. Instead, UPR activation relatively decreased with increasing syncytium formation, an effect that was not observed if cell-cell fusion was blocked. These results support the idea that syncytium formation limits UPR activation despite ongoing viral glycoprotein synthesis. This as yet undescribed mechanism is likely a fusion-dependent countermeasure to prevent an overload of the ER folding capacity by dilution and suggests that NiV-induced syncytium formation not only is an important way to promote NiV spread from cell-to-cell but also regulates ER stress to limit potential UPR-induced antiviral responses.IMPORTANCEThe unfolded protein response (UPR) is a cellular signaling pathway to counteract ER stress. Many enveloped viruses, which force the infected cell to synthesize high amounts of viral surface glycoproteins, induce the UPR but regulate its activation by diverse strategies to prevent UPR-mediated antiviral effects. To date, nothing is known about UPR activation in infections with Nipah virus (NiV), a highly pathogenic member of the