Structural insights into the nairovirus nucleoprotein endonuclease activity.

Area of Science:

• Virology
• Molecular Biology
• Biochemistry

Background:

• Nairoviruses are emerging tick-borne pathogens lacking effective antiviral treatments.
• Viral nucleoproteins (NPs) are crucial for genome encapsulation, but their additional functions in replication are largely unknown.

Purpose of the Study:

• To investigate the functions of Tacheng tick virus 1 (TcTV1) nucleoprotein (NP).
• To explore the potential of targeting nairovirus NP for antiviral drug development.

Main Methods:

• Biochemical assays to study TcTV1 NP's nucleic acid binding and endonuclease activity.
• Structural analysis of NP assembly and conformational changes.
• Functional analysis of the NP stalk domain.
• Screening for small-molecule inhibitors targeting NP.

Main Results:

• TcTV1 NP binds nucleic acids independently of sequence and forms tetramer-based ribonucleoprotein complexes.
• NP undergoes conformational changes facilitating polymerization and exhibits metal-ion-independent endonuclease activity against unstructured single-stranded RNA.
• The NP stalk domain is critical for RNA binding, oligomerization, and nuclease activity regulation.
• A small-molecule compound was identified that inhibits both RNA binding and nuclease activity by targeting a conserved NP region.

Conclusions:

• Nairovirus NPs possess an expanded functional repertoire beyond RNA encapsulation, including sequence-independent RNA binding and ssRNA-specific endonuclease activity.
• NP-mediated RNA discrimination may play a role in viral replication.
• Targeting conserved functional regions of nairovirus NP presents a viable strategy for developing novel antiviral therapies against emerging nairoviruses.