SARS Coronavirus Papain-Like Protease Inhibits the TLR7 Signaling Pathway through Removing Lys63-Linked Polyubiquitination of TRAF3 and TRAF6

Li, Shih Wen; Wang, Ching Ying; Jou, Yu Jen; Huang, Su; Hsiao, Li Hsin; Wan, Lei; Lin, Ying; Kung, Szu Hao; Lin, Cheng Wen

doi:10.3390/ijms17050678

Cited by 139 publications

(139 citation statements)

References 27 publications

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“…The SARS‐CoV PL pro removes Lys63‐linked ubiquitin (Ub) chains from TRAF3 and TRAF6 to reduce the TLR7‐mediated immune signaling . Furthermore, the SARS‐CoV PL pro cannot remove Lys48‐linked Ub chains from TRAF3 and TRAF6 according to a western blot assay . This is at variance with an in vitro study that demonstrated that SARS‐CoV PL pro prefers to process Lys48‐ over Lys63‐linked polyUb chains .…”

Section: Rna‐virus Proteases Interfering With the Host Innate Immunementioning

confidence: 90%

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RNA‐virus proteases counteracting host innate immunity

Lei

Hilgenfeld

2017

FEBS Letters

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Virus invasion triggers host immune responses, in particular, innate immune responses. Pathogen‐associated molecular patterns of viruses (such as dsRNA, ssRNA, or viral proteins) released during virus replication are detected by the corresponding pattern‐recognition receptors of the host, and innate immune responses are induced. Through production of type‐I and type‐III interferons as well as various other cytokines, the host innate immune system forms the frontline to protect host cells and inhibit virus infection. Not surprisingly, viruses have evolved diverse strategies to counter this antiviral system. In this review, we discuss the multiple strategies used by proteases of positive‐sense single‐stranded RNA viruses of the families Picornaviridae, Coronaviridae, and Flaviviridae, when counteracting host innate immune responses.

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Section: Rna‐virus Proteases Interfering With the Host Innate Immunementioning

confidence: 90%

Section: Rna‐virus Proteases Interfering With the Host Innate Immunementioning

confidence: 99%

RNA‐virus proteases counteracting host innate immunity

Lei

Hilgenfeld

2017

FEBS Letters

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“…SARS-CoV PL2 pro plus TM can also physically interact with the STING-TRAF3-TBK1 complex and remove the ubiquitins from ubiquitinated RIG-I, STING, TRAF3, TBK1, as well as IRF3 . In 2016, it was reported that the SARS-CoV PL2 pro can inhibit the Toll-like receptor 7 (TLR7)-mediated type-I IFN response and the NF-κB pathway by removing the Lys63-linked polyUb chain from TRAF3 and TRAF6 (upstream regulators of IRF3 and NF-κB;Li et al, 2016b). Interestingly, the SARS-CoV PL2 pro only removes the Lys63-but not the Lys48-linked polyUb chain from TRAF3 and TRAF6 in vivo (Li et al, 2016b).…”

Section: Papain-like Protease 2 (Pl2 Pro )mentioning

confidence: 99%

“…In 2016, it was reported that the SARS-CoV PL2 pro can inhibit the Toll-like receptor 7 (TLR7)-mediated type-I IFN response and the NF-κB pathway by removing the Lys63-linked polyUb chain from TRAF3 and TRAF6 (upstream regulators of IRF3 and NF-κB;Li et al, 2016b). Interestingly, the SARS-CoV PL2 pro only removes the Lys63-but not the Lys48-linked polyUb chain from TRAF3 and TRAF6 in vivo (Li et al, 2016b). On the other hand, Báez-Santos et al (2014) and Békés et al (2015Békés et al ( , 2016 have shown that SARS-CoV PL2 pro prefers to digest Lys48over Lys63-linked polyUb chains in vitro (see above).…”

Section: Papain-like Protease 2 (Pl2 Pro )mentioning

confidence: 99%

Nsp3 of coronaviruses: Structures and functions of a large multi-domain protein

2018

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The multi-domain non-structural protein 3 (Nsp3) is the largest protein encoded by the coronavirus (CoV) genome, with an average molecular mass of about 200 kD. Nsp3 is an essential component of the replication/transcription complex. It comprises various domains, the organization of which differs between CoV genera, due to duplication or absence of some domains. However, eight domains of Nsp3 exist in all known CoVs: the ubiquitin-like domain 1 (Ubl1), the Glu-rich acidic domain (also called "hypervariable region"), a macrodomain (also named "X domain"), the ubiquitin-like domain 2 (Ubl2), the papain-like protease 2 (PL2), the Nsp3 ectodomain (3Ecto, also called "zinc-finger domain"), as well as the domains Y1 and CoV-Y of unknown functions. In addition, the two transmembrane regions, TM1 and TM2, exist in all CoVs. The three-dimensional structures of domains in the N-terminal two thirds of Nsp3 have been investigated by X-ray crystallography and/or nuclear magnetic resonance (NMR) spectroscopy since the outbreaks of Severe Acute Respiratory Syndrome coronavirus (SARS-CoV) in 2003 as well as Middle-East Respiratory Syndrome coronavirus (MERS-CoV) in 2012. In this review, the structures and functions of these domains of Nsp3 are discussed in depth.

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“…PLpro, a de-ubiquitinating/de-ISGylating enzyme (Barretto et al, 2005;Ratia et al, 2006), has the antagonistic activities of Type I interferon (IFN) via blocking IRF-3 and ERK1 phosphorylation, preventing the IκBα degradation, and de-ubiquitinating the STING-TRAF3-TBK1 complex (Li et al, 2011;Frieman et al, 2009;Sun et al, 2012). Recently, PLpro shows the inhibitory effect on Tolllike receptor 7 (TLR7) mediated cytokine production through removing Lys63-linked ubiquitin chains of TRAF3 and TRAF6 (Li et al, 2016a).…”

Section: Introductionmentioning

confidence: 99%

SARS coronavirus papain-like protease up-regulates the collagen expression through non-Samd TGF-β1 signaling

Wang

et al. 2017

Virus Research

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SARS coronavirus (CoV) papain-like protease (PLpro) reportedly induced the production of TGF-β1 through p38 MAPK/STAT3-meidated Egr-1-dependent activation (Sci. Rep. 6, 25754). This study investigated the correlation of PLpro-induced TGF-β1 with the expression of Type I collagen in human lung epithelial cells and mouse pulmonary tissues. Specific inhibitors for TGF-βRI, p38 MAPK, MEK, and STAT3 proved that SARS-CoV PLpro induced TGF-β1-dependent up-regulation of Type I collagen in vitro and in vivo. Subcellular localization analysis of SMAD3 and SMAD7 indicated that non-SMAD pathways in TGF-β1 signaling involved in the production of Type I collagen in transfected cells with pSARS-PLpro. Comprehensive analysis of ubiquitin-conjugated proteins using immunoprecipitation and nanoLC-MS/MS indicated that SARS-CoV PLpro caused the change in the ubiquitination profile of Rho GTPase family proteins, in which linked with the increase of Rho-like GTPase family proteins. Moreover, selective inhibitors TGF-βRI and STAT6 (AS1517499) ascertained that STAT6 activation was required for PLpro-induced TGF-β1-dependent up-regulation of Type I collagen in human lung epithelial cells. The results showed that SARS-CoV PLpro stimulated TGF-β1-dependent expression of Type I collagen via activating STAT6 pathway.

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SARS Coronavirus Papain-Like Protease Inhibits the TLR7 Signaling Pathway through Removing Lys63-Linked Polyubiquitination of TRAF3 and TRAF6

Cited by 139 publications

References 27 publications

RNA‐virus proteases counteracting host innate immunity

RNA‐virus proteases counteracting host innate immunity

Nsp3 of coronaviruses: Structures and functions of a large multi-domain protein

SARS coronavirus papain-like protease up-regulates the collagen expression through non-Samd TGF-β1 signaling

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