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Secretory glycoprotein NS1 plays a crucial role in the particle formation of flaviviruses

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Title: Secretory glycoprotein NS1 plays a crucial role in the particle formation of flaviviruses
Authors: Tamura, Tomokazu Browse this author
Torii, Shiho Browse this author
Kajiwara, Kentaro Browse this author
Anzai, Itsuki Browse this author
Fujioka, Yoichiro Browse this author →KAKEN DB
Noda, Kisho Browse this author
Taguwa, Shuhei Browse this author
Morioka, Yuhei Browse this author
Suzuki, Rigel Browse this author
Fauzyah, Yuzy Browse this author
Ono, Chikako Browse this author
Ohba, Yusuke Browse this author →KAKEN DB
Okada, Masato Browse this author
Fukuhara, Takasuke Browse this author →KAKEN DB
Matsuura, Yoshiharu Browse this author
Issue Date: 3-Jun-2022
Publisher: PLOS
Journal Title: PLoS pathogens
Volume: 18
Issue: 6
Start Page: e1010593
Publisher DOI: 10.1371/journal.ppat.1010593
Abstract: Flaviviruses, which are globally distributed and cause a spectrum of potentially severe illnesses, pose a major threat to public health. Although Flaviviridae viruses, including flaviviruses, possess similar genome structures, only the flaviviruses encode the non-structural protein NS1, which resides in the endoplasmic reticulum (ER) and is secreted from cells after oligomerization. The ER-resident NS1 is known to be involved in viral genome replication, but the essential roles of secretory NS1 in the virus life cycle are not fully understood. Here we characterized the roles of secretory NS1 in the particle formation of flaviviruses. We first identified an amino acid residue essential for the NS1 secretion but not for viral genome replication by using protein-protein interaction network analyses and mutagenesis scanning. By using the recombinant flaviviruses carrying the identified NS1 mutation, we clarified that the mutant flaviviruses employed viral genome replication. We then constructed a recombinant NS1 with the identified mutation and demonstrated by physicochemical assays that the mutant NS1 was unable to form a proper oligomer or associate with liposomes. Finally, we showed that the functions of NS1 that were lost by the identified mutation could be compensated for by the in trans-expression of E-rns of pestiviruses and host exchangeable apolipoproteins, which participate in the infectious particle formation of pestiviruses and hepaciviruses in the family Flaviviridae, respectively. Collectively, our study suggests that secretory NS1 plays a role in the particle formation of flaviviruses through its interaction with the lipid membrane. Author summaryIt is difficult to characterize the function of NS1 in the post-genome replication stages in the virus life cycle of flaviviruses. Here, by means of protein-protein interaction network analyses and mutagenesis scanning, we identified a unique mutation in NS1 by which the protein loses its secretory capacity while retaining its genome replication activity. Physicochemical assays using the mutant NS1 revealed that oligomerization of NS1 is responsible for the lipid association and secretion of NS1. In addition, we established a complementation assay that can evaluate the particle formation of Flaviviridae viruses. By using recombinant flaviviruses possessing the identified mutation in NS1, we clarified that NS1 is involved in particle formation. Our findings reveal that the flavivirus NS1 has at least two roles in the virus life cycles-namely, a role in infectious particle formation and a role in viral genome replication.
Type: article
Appears in Collections:医学院・医学研究院 (Graduate School of Medicine / Faculty of Medicine) > 雑誌発表論文等 (Peer-reviewed Journal Articles, etc)

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