The N-terminal domain of Npro 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 (2015). The N-terminal domain of Npro of classical swine fever virus determines its stability and regulates type I IFN production. Journal of general virology, 96(Pt 7), pp. 1746-1756. Society for General Microbiology 10.1099/vir.0.000132

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The viral protein Npro is unique to the genus Pestivirus within the family Flaviviridae. After autocatalytic cleavage from the nascent polyprotein, Npro suppresses type I IFN (IFN-α/β) induction by mediating proteasomal degradation of IFN regulatory factor 3 (IRF-3). Previous studies found that the Npro-mediated IRF-3 degradation was dependent of a TRASH domain in the C-terminal half of Npro coordinating zinc by means of the amino acid residues C112, C134, 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-α/β 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 Npro 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 Npro contributed to higher stability of the reconstructed Npro compared with the Npro from the Thai isolate. This led to enhanced interaction of Npro 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 Npro are involved in the stability of Npro, in interaction of Npro with IRF-3 and subsequent degradation of IRF-3, leading to downregulation of IFN-α/β production.

Item Type:

Journal Article (Original Article)

Division/Institute:

05 Veterinary Medicine > Research Foci > Host-Pathogen Interaction
05 Veterinary Medicine > Department of Infectious Diseases and Pathobiology (DIP) > Institute of Virology and Immunology
05 Veterinary Medicine > Department of Infectious Diseases and Pathobiology (DIP)

UniBE Contributor:

Ruggli, Nicolas

Subjects:

600 Technology > 630 Agriculture

ISSN:

0022-1317

Publisher:

Society for General Microbiology

Language:

English

Submitter:

Barbara Gautschi-Steffen

Date Deposited:

29 Feb 2016 15:00

Last Modified:

29 Feb 2016 15:00

Publisher DOI:

10.1099/vir.0.000132

PubMed ID:

25809915

URI:

https://boris.unibe.ch/id/eprint/76063

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