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The N-terminal domain of N-pro of classical swine fever virus determines its stability and regulates type I IFN production

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Title: The N-terminal domain of N-pro of classical swine fever virus determines its stability and regulates type I IFN production
Authors: Mine, Junki Browse this author
Tamura, Tomokazu Browse this author
Mitsuhashi, Kazuya Browse this author
Okamatsu, Masatoshi Browse this author →KAKEN DB
Parchariyanon, Sujira Browse this author
Pinyochon, Wasana Browse this author
Ruggli, Nicolas Browse this author
Tratschin, Jon-Duri Browse this author
Kida, Hiroshi Browse this author →KAKEN DB
Sakoda, Yoshihiro Browse this author →KAKEN DB
Keywords: CSFV
Issue Date: Jul-2015
Publisher: Society for General Microbiology
Journal Title: Journal of General Virology
Volume: 96
Issue: 7
Start Page: 1746
End Page: 1756
Publisher DOI: 10.1099/vir.0.000132
PMID: 25809915
Abstract: The viral protein N-pro is unique to the genus Pestivirus within the family Flaviviridae. After autocatalytic cleavage from the nascent polyprotein, N-pro suppresses type I IFN (IFN-alpha/beta) induction by mediating proteasomal degradation of IFN regulatory factor 3 (IRF-3). Previous studies found that the N-pro-mediated IRF-3 degradation was dependent of a TRASH domain in the C-terminal half of N-pro coordinating zinc by means of the amino acid residues 0112, 0134, D136 and C138. Interestingly, four classical swine fever virus (CSFV) isolates obtained from diseased pigs in Thailand in 1993 and 1998 did not suppress IFN-alpha/beta induction despite the presence of an intact TRASH domain. Through systematic analyses, it was found that an amino acid mutation at position 40 or mutations at positions 17 and 61 in the N-terminal half of N-pro of these four isolates were related to the lack of IRF-3-degrading activity. restoring a histidine at position 40 or both a proline at position 17 and a lysine at position 61 based on the sequence of a functional N-pro contributed to higher stability of the reconstructed N-pro compared with the N-pro from the Thai isolate. This led to enhanced interaction of N-pro with IRF-3 along with its degradation by the proteasome. The results of the present study revealed that amino acid residues in the N-terminal domain of N-pro are involved in the stability of N-pro, in interaction of N-pro with IRF-3 and subsequent degradation of IRF-3, leading to downregulation of IFN-alpha/beta production.
Type: article (author version)
Appears in Collections:獣医学院・獣医学研究院 (Graduate School of Veterinary Medicine / Faculty of Veterinary Medicine) > 雑誌発表論文等 (Peer-reviewed Journal Articles, etc)

Submitter: 迫田 義博

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