Macrodomain ADP-ribose binding but not ADP-ribosylhydrolase activity is critical for chikungunya virus infection of <i>Aedes</i> mosquitoes.

ABSTRACT: Viral macrodomains are promising antiviral targets that counteract host ADP-ribosylation-mediated antiviral responses in mammals. However, their role in dual-host viruses within the mosquito vector is largely unknown. Here, we investigated the role of the chikungunya virus (CHIKV) macrodomain by mutating the active site asparagine 24 (N24). In both mammalian and mosquito cell lines, these enzymes rapidly acquired compensatory mutations at aspartate 31 (D31). We show that while N24 mutations abolish ADP-ribosylhydrolase catalytic activity and reduce folding stability, ADP-ribose binding remains intact. Furthermore, the D31 compensatory mutations do not markedly rescue catalytic activity or folding stability. Structures of the compensatory mutant macrodomains suggest the importance of ADP-ri

SUBMITTER: Bardossy ES 

PROVIDER: S-EPMC12632316 | biostudies-literature | 2025 Oct

REPOSITORIES: biostudies-literature