Researchers Reveal Mechanism of Arenavirus Replication Machinery (Biology)

Arenaviruses encode their own RNA-dependent RNA polymerase (RdRp), namely the L protein, for replication and transcription of the viral genome, and this molecule is quite conserved among different viral species, which indicates a very important antiviral therapeutic target.

Z protein has been revealed to interact with the polymerase to inhibit RNA synthesis at the late stage of viral replication, initiating the assembly of progeny virions. Therefore, elucidating the working mechanism of arenavirus polymerase and the regulatory mechanism of Z protein for the polymerase activity is of great significance for developing specific and broad-spectrum antiviral drugs.

In a study published in Nature Microbiology, SHI Yi’s lab at the Institute of Microbiology of the Chinese Academy of Sciences investigated the mechanism of arenavirus matrix protein Z regulating the polymerase activity.

In 2020, SHI’s lab reported the first near-atomic resolution structure of arenavirus polymerase, as well as its complex with viral RNA (vRNA) promoter. The findings constitute a basic framework for understanding the mechanism of arenavirus replication, but yet many further questions remain.

In this new study, the researchers determined the structures of Lassa virus (LASV) and Machupo mammarenavirus (MACV) L proteins in complex with their cognate Z proteins, and the ternary complexes of L-Z-vRNA.

These structures revealed that the Z protein binds to the periphery of palm domain of RdRp, far away from the binding site of vRNA. Therefore, the binding of Z protein does not prevent vRNA recruitment by the L polymerase. Despite no catalytic residues being directly engaged by Z protein, the distal ends of two catalytic motifs are involved in interactions with Z protein outside the catalytic center. These binding motifs are located at the interface between multiple domains. The binding of Z protein would restrict the conformational changes of key catalytic motifs required for catalysis, resulting in inactivation of the polymerase.

Besides, looking into the L-Z contacting interface, the researchers found that Z protein binds to the L protein through its central domain, in which a highly conserved hydrophobic loop dominates the interaction with the L polymerase. Because of the conservation of the dominant binding motif, they observed that LASV and MACV Z proteins could cross-inhibit the activity of heterologous L polymerases. This observation is quite remarkable. This indicated the regulatory effect of Z protein on polymerase might be a universal mechanism among all arenaviruses, and suggested the possibility of cross-inhibition between different viruses.

These findings provide a new strategy for developing broad-spectrum antiviral drugs against different arenaviruses.

Arenaviruses are a group of enveloped and segmented negative-sense RNA viruses (sNSVs), comprising the family Arenaviridae. All human-infecting arenaviruses belong to the genus mammarenavirus, exemplified by LASV. Unfortunately, there are no specific drugs or vaccines available for most arenavirus infections, posing great challenges for the treatments of related diseases.

Reference: Xu, X., Peng, R., Peng, Q. et al. Cryo-EM structures of Lassa and Machupo virus polymerases complexed with cognate regulatory Z proteins identify targets for antivirals. Nat Microbiol (2021).

Provided by Chinese Academy of Sciences

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