Keap1 recognizes EIAV early accessory protein Rev to promote antiviral defense

Wang, Y.; Ma, G.; Wang, X.-F.; Na, L.; Guo, X.; Zhang, J.; Liu, C.; Du, C.; Lin, Y.; Wang, X.

doi:10.1101/2021.09.29.462336

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bioRxiv · 10.1101/2021.09.29.462336

Keap1 recognizes EIAV early accessory protein Rev to promote antiviral defense

Wang, Y.·Ma, G.·Wang, X.-F.·Na, L.·Guo, X.·Zhang, J.·Liu, C.·Du, C.·Lin, Y.·Wang, X.

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Abstract

The Nrf2/Keap1 axis plays a complex role in viral susceptibility, virus-associated inflammation and immune regulation. However, whether or how the Nrf2/Keap1 axis is involved in the interactions between equine lentiviruses and their hosts remains unclear. Here, we demonstrate that the Nrf2/Keap1 axis was activated during EIAV infection. Mechanistically, EIAV-Rev competitively binds to Keap1 and releases Nrf2 from Keap1-mediated repression, leading to the accumulation of Nrf2 in the nucleus and promoting Nrf2 responsive genes transcription. Subsequently, we demonstrated that the Nrf2/Keap1 axis represses EIAV replication via two independent molecular mechanisms: directly increasing antioxidant enzymes to promote effective cellular resistance against EIAV infection, and repression of Rev-mediated RNA transport through direct interaction between Keap1 and Rev. Together, these data suggest that activation of the Nrf2/Keap1 axis mediates a passive defensive response to combat EIAV infection. The Nrf2/Keap1 axis could be a potential target for developing the strategies for combating EIAV infection. Author summaryHere we report that the Nrf2/Keap1 axis acts as an antiviral effector on EIAV replication through two-way regulation of Rev. On the one hand, EIAV-Rev activates the Nrf2/Keap1 axis by competitive interaction with Keap1, which promotes the transcription of cytoprotective genes implicated in the antiviral response. On the other hand, Keap1 restricts Rev/RRE-dependent RNA transport, leading to inhibition of viral protein synthesis and reduction in viral replication. This study highlights the importance of the Nrf2/Keap1 axis in controlling EIAV replication, and identifies this pathway as a potential new entry-point for treating lentivirus infection. Importantly, this report provides new insights into the regulation of viral replication by the Nrf2/Keap1 axis.

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Wang, Y., Ma, G., Wang, X.-F., Na, L., Guo, X., Zhang, J., Liu, C., Du, C., Lin, Y., Wang, X.. 2021-09-29. Keap1 recognizes EIAV early accessory protein Rev to promote antiviral defense. https://doi.org/10.1101/2021.09.29.462336

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