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

Wang, Dan; Fang, Liurong; Li, Ping; Sun, Li; Fan, Jinxiu; Zhang, Qingye; Luo, Rui; Liu, Xiangtao; Li, Kui; Chen, Huanchun; Chen, Zhongbin; Xiao, Shaobo

doi:10.1128/jvi.02589-10

Cited by 168 publications

(184 citation statements)

References 55 publications

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“…We have reported that human CoV NL63 and SARS PLpro reduce the ubiquitinated forms of STING, RIG-I, TBK1 and IRF3 in cells (Sun et al, 2012). It is interesting that coronaviruses, including human CoV NL63, SARS-CoV, transmissible gastroenteritis virus, murine hepatitis virus and PEDV reported here, have evolved to encode DUBs (Barretto et al, 2005;Clementz et al, 2010;Lindner et al, 2005; (Wang et al, 2011a), human cytomegalovirus UL48 (Kim et al, 2009), herpes simplex virus type 1 UL36 (Kattenhorn et al, 2005), porcine reproductive and respiratory syndrome virus nsp2 Sun et al, 2010b).…”

Section: Discussionmentioning

confidence: 99%

The papain-like protease of porcine epidemic diarrhea virus negatively regulates type I interferon pathway by acting as a viral deubiquitinase

Xing

Chen

et al. 2013

Journal of General Virology

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145

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Porcine epidemic diarrhea virus (PEDV) is the cause of an economically important swine disease. Previous studies suggested that PEDV does not elicit a robust IFN response, but the mechanism(s) used to evade or block this innate immune response was not known. In this study, we found that PEDV infection blocked synthetic dsRNA-induced IFN-b production by interfering with the activation of interferon regulatory factor 3 (IRF3). We identified PEDV replicase encoded papain-like protease 2 (PLP2) as an IFN antagonist that depends on catalytic activity for its function. We show that levels of ubiquitinated proteins are reduced during PEDV infection and that PEDV PLP2 has deubiquitinase (DUB) activity that recognizes and processes both K-48 and K-63 linked polyubiquitin chains. Furthermore, we found that PEDV PLP2 strongly inhibits RIG-Iand STING-activated IFN expression and that PEDV PLP2 can be co-immunoprecipitated with and deubiquitinates RIG-I and STING, the key components of the signalling pathway for IFN expression. These results show that PEDV infection suppresses production of IFN-b and provides evidence indicating that the PEDV papain-like protease 2 acts as a viral DUB to interfere with the RIG-I-and STING-mediated signalling pathway.

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Section: Discussionmentioning

confidence: 99%

The papain-like protease of porcine epidemic diarrhea virus negatively regulates type I interferon pathway by acting as a viral deubiquitinase

Xing

Chen

et al. 2013

Journal of General Virology

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145

170

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“…Whereas canonical IKKs have long been recognized as bridges between chronic inflammation and cancer, IKK-related kinases more recently have also been implicated in cell transformation and tumor progression (13). TBK1 has been of particular interest, given its identification both as an activator of the oncogenic AKT kinase (14)(15)(16)(17)(18) and as an essential factor in KRAS-driven cancers (19). TBK1 activity is regulated by phosphorylation on S172 within the classical kinase activation loop.…”

mentioning

confidence: 99%

Molecular basis of Tank-binding kinase 1 activation by transautophosphorylation

Ma¹,

Helgason

Phung³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

188

227

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Tank-binding kinase (TBK)1 plays a central role in innate immunity: it serves as an integrator of multiple signals induced by receptormediated pathogen detection and as a modulator of IFN levels. Efforts to better understand the biology of this key immunological factor have intensified recently as growing evidence implicates aberrant TBK1 activity in a variety of autoimmune diseases and cancers. Nevertheless, key molecular details of TBK1 regulation and substrate selection remain unanswered. Here, structures of phosphorylated and unphosphorylated human TBK1 kinase and ubiquitin-like domains, combined with biochemical studies, indicate a molecular mechanism of activation via transautophosphorylation. These TBK1 structures are consistent with the tripartite architecture observed recently for the related kinase IKKβ, but domain contributions toward target recognition appear to differ for the two enzymes. In particular, both TBK1 autoactivation and substrate specificity are likely driven by signal-dependent colocalization events. Phosphorylation promotes the dimerization and nuclear translocation of these transcription factors that stimulate production of type I interferons (IFNs) (1,3,5). Recent studies have identified an additional role for TBK1 in the xenophagic elimination of bacteria (6-9) and better-defined how cross-talk within the IKK family regulates innate immune response (10).Under pathological conditions, IKK-mediated pathways can also be activated inappropriately by endogenous signals, contributing to inflammatory disorders and oncogenesis (11,12). Whereas canonical IKKs have long been recognized as bridges between chronic inflammation and cancer, IKK-related kinases more recently have also been implicated in cell transformation and tumor progression (13). TBK1 has been of particular interest, given its identification both as an activator of the oncogenic AKT kinase (14-18) and as an essential factor in KRAS-driven cancers (19).TBK1 activity is regulated by phosphorylation on S172 within the classical kinase activation loop. Serine-to-alanine substitution at this position abolishes TBK1 activity, whereas the phosphomimetic mutation S172E partially restores activity to within ∼200-fold of the wild-type kinase (20). Genetic and pharmacological inhibition studies have indicated that TBK1 can be activated by IKKβ, as well as by apparent autophosphorylation (10). Additional posttranslational modifications of TBK1 lysine residues by K63-linked polyubiquitin chains have been shown to promote production of IFNs in viral infections (21).TBK1 contains a predicted ubiquitin-like domain (ULD) (22) that is located between the N-terminal kinase domain (KD) and the C-terminal scaffolding/dimerization domain (SDD), a domain arrangement that appears to be shared among the IKK family of kinases (3). Deletion or mutation of the ULD in TBK1 or IKKε severely impairs kinase activation and substrate phosphorylation in cells (22,23). Furthermore, the integrity of the ULD in IKKβ is not only required for kinase activity (24) bu...

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“…A number of viruses encode deubiquitination enzymes (DUBs) to manipulate cellular processes, and several virally encoded DUBs have been shown to antagonize IFN signaling (13,28,30,34). Recently, a number of studies have shown that herpesviridae have large tegument proteins with a DUB domain embedded at their N terminus, such as herpes simplex virus 1 (HSV-1) UL36 USP , mouse cytomegalovirus (MCMV) M48, human cytomegalovirus (HCMV) UL48, EBV BPLF1, and KSHV and MHV68 ORF64 (11,14,25,26,31).…”

mentioning

confidence: 99%

Inhibition of RIG-I-Mediated Signaling by Kaposi's Sarcoma-Associated Herpesvirus-Encoded Deubiquitinase ORF64

Inn

Lee

Rathbun

et al. 2011

J Virol

143

150

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

Cited by 168 publications

References 55 publications

The papain-like protease of porcine epidemic diarrhea virus negatively regulates type I interferon pathway by acting as a viral deubiquitinase

The papain-like protease of porcine epidemic diarrhea virus negatively regulates type I interferon pathway by acting as a viral deubiquitinase

Molecular basis of Tank-binding kinase 1 activation by transautophosphorylation

Inhibition of RIG-I-Mediated Signaling by Kaposi's Sarcoma-Associated Herpesvirus-Encoded Deubiquitinase ORF64

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