AI Article Synopsis
- Viruses have evolved mechanisms to break down cellular proteins to enhance their infection and disease-causing ability, and the non-structural protein NSs from Rift Valley fever virus plays a crucial role in this process.
- The NSs protein forms helical structures that work as an E3 ligase, specifically targeting and degrading the TFIIH complex, which is important for antiviral immunity.
- The degradation of the TFIIH complex by NSs leads to a significant weakening of the host's immune response and facilitates the virus's ability to cause disease, while also showing potential for targeting other proteins in the cell.
Article Abstract
Viruses encode strategies to degrade cellular proteins to promote infection and pathogenesis. Here, we revealed that the non-structural protein NSs of Rift Valley fever virus forms a filamentous E3 ligase to trigger efficient degradation of targeted proteins. Reconstitution in vitro and cryoelectron microscopy analysis with the 2.9-Å resolution revealed that NSs forms right-handed helical fibrils. The NSs filamentous oligomers associate with the cellular FBXO3 to form a remodeled E3 ligase. The NSs-FBXO3 E3 ligase targets the cellular TFIIH complex through the NSs-P62 interaction, leading to ubiquitination and proteasome-dependent degradation of the TFIIH complex. NSs-FBXO3-triggered TFIIH complex degradation resulted in robust inhibition of antiviral immunity and promoted viral pathogenesis in vivo. Furthermore, it is demonstrated that NSs can be programmed to target additional proteins for proteasome-dependent degradation, serving as a versatile targeted protein degrader. These results showed that a virulence factor forms a filamentous and programmable degradation machinery to induce organized degradation of cellular proteins to promote viral infection.
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| http://dx.doi.org/10.1016/j.cell.2024.09.008 | DOI Listing |
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