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

Mine, Junki  ,  Tamura, Tomokazu  ,  Mitsuhashi, Kazuya  ,  Okamatsu, Masatoshi  ,  Parchariyanon, Sujira  ,  Pinyochon, Wasana  ,  Ruggli, Nicolas  ,  Tratschin, Jon-Duri  ,  Kida, Hiroshi  ,  Sakoda, Yoshihiro

96 ( 7 )  , pp.1746 - 1756 , 2015-07 , Society for General Microbiology
ISSN:0022-13171465-2099
NCID:AA00698722
Description
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.
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http://eprints.lib.hokudai.ac.jp/dspace/bitstream/2115/62343/1/Supplementary%20Data.pdf

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