Rift Valley fever virus coordinates the assembly of a programmable E3 ligase to promote viral replication

Area of Science:

• Virology
• Molecular Biology
• Structural Biology

Background:

• Viruses utilize protein degradation to facilitate infection and pathogenesis.
• Understanding viral strategies for manipulating host cell machinery is crucial for developing antiviral therapies.

Purpose of the Study:

• To elucidate the mechanism by which the Rift Valley fever virus non-structural protein NSs induces targeted protein degradation.
• To characterize the structure and function of the NSs-mediated protein degradation complex.

Main Methods:

• In vitro reconstitution assays.
• Cryo-electron microscopy (cryo-EM) at 2.9-Å resolution.
• Ubiquitination and proteasome degradation assays.
• In vivo pathogenesis studies.

Main Results:

• Rift Valley fever virus NSs protein forms right-handed helical fibrils.
• NSs fibrils associate with cellular FBXO3 to create a novel E3 ligase complex.
• This NSs-FBXO3 E3 ligase targets the TFIIH complex for ubiquitination and proteasomal degradation via NSs-P62 interaction.
• Degradation of TFIIH inhibits antiviral immunity and enhances viral pathogenesis.
• NSs demonstrates potential as a programmable targeted protein degrader.

Conclusions:

• The Rift Valley fever virus NSs protein functions as a virulence factor by forming a filamentous, programmable degradation machinery.
• This machinery induces organized degradation of cellular proteins, specifically the TFIIH complex, to promote viral infection and pathogenesis.
• The findings offer insights into viral evasion mechanisms and present NSs as a potential tool for targeted protein degradation applications.