The Leader Proteinase of Foot-and-Mouth Disease Virus Negatively Regulates the Type I Interferon Pathway by Acting as a Viral Deubiquitinase

• DOI: 10.1128/jvi.02589-10
• Publication Date: 2011-02-10T03:11:32Z
• Authors: Dang Wang; Liurong Fang; Ping Li; Li Sun; Jinxiu Fan; Qingye Zhang; Rui Luo; Xiangtao Liu; Kui Li; Huanchun Chen; Zhongbin Chen; Shaobo Xiao
• Keywords: Models, Molecular; 0301 basic medicine; Ubiquitin; Cell Line; 3. Good health; Viral Proteins; 03 medical and health sciences; Foot-and-Mouth Disease Virus; Endopeptidases; Interferon Type I; Humans; Amino Acid Sequence; Conserved Sequence

ABSTRACT

The leader proteinase (L pro ) of foot-and-mouth disease virus (FMDV) is a papain-like proteinase that plays an important role in FMDV pathogenesis. Previously, it has been shown that L pro is involved in the inhibition of the type I interferon (IFN) response by FMDV. However, the underlying mechanisms remain unclear. Here we demonstrate that FMDV Lb pro , a shorter form of L pro , has deubiquitinating activity. Sequence alignment and structural bioinformatics analyses revealed that the catalytic residues (Cys51 and His148) are highly conserved in FMDV Lb pro of all seven serotypes and that the topology of FMDV Lb pro is remarkably similar to that of ubiquitin-specific protease 14 (USP14), a cellular deubiquitylation enzyme (DUB), and to that of severe acute respiratory syndrome coronavirus (SARS-CoV) papain-like protease (PLpro), a coronaviral DUB. Both purified Lb pro protein and in vivo ectopically expressed Lb pro removed ubiquitin (Ub) moieties from cellular substrates, acting on both lysine-48- and lysine-63-linked polyubiquitin chains. Furthermore, Lb pro significantly inhibited ubiquitination of retinoic acid-inducible gene I (RIG-I), TANK-binding kinase 1 (TBK1), TNF receptor-associated factor 6 (TRAF6), and TRAF3, key signaling molecules in activation of type I IFN response. Mutations in Lb pro that ablate the catalytic activity (C51A or D163N/D164N) or disrupt the SAP (for S AF-A/B, A cinus, and P IAS) domain (I83A/L86A) abrogated the DUB activity of Lb pro as well as its ability to block signaling to the IFN-β promoter. Collectively, these results demonstrate that FMDV Lb pro possesses DUB activity in addition to serving as a viral proteinase and describe a novel mechanism evolved by FMDV to counteract host innate antiviral responses.