Membrane tethering by the host ER-resident GTPase Atlastin-2 is critical for flavivirus replication

Using confocal and electron microscopy, we show that ATL2 depletion leads to a reduction in vRO spatial distribution in cells infected with either DENV or ZIKV. Changes in vRO distribution corresponded to a decrease in virus production and robust induction of innate immune responses. We also demonstrate that ATL2 accumulates in areas of vRO formation during flavivirus infection.

ATL2 mutational analysis showed that a tethering-competent but fusion-defective ATL2 mutant was sufficient to rescue DENV and ZIKV replication in ATL2-knockout cells. Finally, inhibition of ATL2 activity using synthetic peptides significantly reduced DENV replication in both cell culture and human primary cells, suggesting a possible avenue for targeting host ER functions to limit flavivirus replication. Taken together, these results show that ATL2 plays a critical and conserved role in flavivirus infection, with its membrane tethering activity functioning to organize membranes for vRO biogenesis.

Importantly, we provide evidence that ATL2 function can be targeted to inhibit viral replication.