Publication Date
12-20-2024
Journal
Science Advances
DOI
10.1126/sciadv.adp9333
PMID
39705355
PMCID
PMC11661447
PubMedCentral® Posted Date
12-20-2024
PubMedCentral® Full Text Version
Post-print
Published Open-Access
yes
Keywords
Norovirus, RNA-Dependent RNA Polymerase, Humans, Virus Replication, RNA, Viral, Biomolecular Condensates, Genome, Viral, Caliciviridae Infections
Abstract
Many viral proteins form biomolecular condensates via liquid-liquid phase separation (LLPS) to support viral replication and evade host antiviral responses, and thus, they are potential targets for designing antivirals. In the case of nonenveloped positive-sense RNA viruses, forming such condensates for viral replication is unclear and less understood. Human noroviruses (HuNoVs) are positive-sense RNA viruses that cause epidemic and sporadic gastroenteritis worldwide. Here, we show that the RNA-dependent RNA polymerase (RdRp) of pandemic GII.4 HuNoV forms distinct condensates that exhibit all the signature properties of LLPS with sustained polymerase activity and the capability of recruiting components essential for viral replication. We show that such condensates are formed in HuNoV-infected human intestinal enteroid cultures and are the sites for genome replication. Our studies demonstrate the formation of phase-separated condensates as replication factories in a positive-sense RNA virus, which plausibly is an effective mechanism to dynamically isolate RdRp replicating the genomic RNA from interfering with the ribosomal translation of the same RNA.
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