DENV Inhibits Type I IFN Production in Infected Cells by Cleaving Human STING

Aguirre, Sebastián; Maestre, Ana; Pagni, Sarah; Patel, Jenish; Savage, Timothy J.; Gutman, Delia; Maringer, Kevin; Bernal-Rubio, Dabeiba; Shabman, Reed S.; Simon, Viviana; Rodríguez-Madoz, Juan R.; Mulder, Lubbertus C. F.; Barber, Glen N.; Fernández-Sesma, Ana

doi:10.1371/journal.ppat.1002934

Cited by 433 publications

(483 citation statements)

References 55 publications

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“…MITA is also a target molecule for microbial pathogens to escape the innate immune response. It has been shown that yellow fever virus, dengue virus, and hepatitis C virus nonstructure proteins target MITA to suppress MITA-mediated IFN induction (29)(30)(31)(32).…”

mentioning

confidence: 99%

An Alternative Splicing Isoform of MITA Antagonizes MITA-Mediated Induction of Type I IFNs

Chen

Pei

Zhu

et al. 2014

The Journal of Immunology

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Mediator of IFN regulatory transcription factor 3 activation (MITA) is an important adaptor protein to mediate the induction of type I IFNs. In this study, we identified an alternatively spliced isoform of MITA lacking exon 7, termed MITA-related protein (MRP). MRP shares the N-terminal portion aa 1–253 with MITA but possesses a unique 30-aa sequence at the carboxyl terminal part, therefore lacking the conserved domains including TANK-binding kinase 1 (TBK1) and cyclic diguanylate binding domain. MRP is expressed in multiple tissues and distinct cell lines. Overexpression of MRP inhibited MITA-mediated activation of IFN-β promoter by sendai virus infection and cyclic diguanylate treatment but enhanced that in HSV-1 infection. Interestingly, MRP expression was reduced after Sendai virus infection but was upregulated after HSV-1 infection. Overexpression of MRP inhibited MITA-mediated induction of IFN-β via TBK1-IFN regulatory transcription factor 3 by disrupting the MITA-TBK1 interaction. However, NF-κB pathway was still activated by MRP, as MRP retained the ability to interact with inducible inhibitor of NF-κB (iκB) kinase. Thus, MRP acts as a dominant negative regulator of MITA-mediated induction of IFN production.

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confidence: 99%

An Alternative Splicing Isoform of MITA Antagonizes MITA-Mediated Induction of Type I IFNs

Chen

Pei

Zhu

et al. 2014

The Journal of Immunology

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“…Differences in the ability of flaviviruses to counteract the type I IFN response between human and mouse cells have previously been reported (27)(28)(29). Phosphorylation of STAT1 and STAT2 proteins was previously shown to be blocked in human cells infected with natural strains of WNV (30)(31)(32), but STAT1 and STAT2 phosphorylation were not inhibited in the mouse cells ( Fig.…”

Section: Resultsmentioning

confidence: 73%

“…Data from several studies have shown that counteraction of the host type I IFN response by flavivirus proteins differs between human and mouse cells. For example, dengue virus is able to counteract human but not mouse STAT2 and STING (27)(28)(29). Previous studies reported that an A30P substitution in the Kunjin WNV NS2A protein abrogated its ability to inhibit IFN signaling and attenuated rather than enhanced its virulence in mice (41).…”

Section: Discussionmentioning

confidence: 99%

Increased Early RNA Replication by Chimeric West Nile Virus W956IC Leads to IPS-1-Mediated Activation of NF-κB and Insufficient Virus-Mediated Counteraction of the Resulting Canonical Type I Interferon Signaling

Scherbik

Pulit-Penaloza

Basu

et al. 2013

J Virol

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, and produced lower virus yields than WNV strain Eg101. IPS-1 was required for both increased induction of IFN-␤ and decreased yields of W956IC. In Eg101-infected cells, phospho-STAT1/STAT2 nuclear translocation was blocked at all times analyzed, while some phospho-STAT1/STAT2 nuclear translocation was still detected at 8 h after infection in W956IC-infected mouse embryonic fibroblasts (MEFs), and early viral protein levels were lower in these cells. A set of additional chimeras was made by replacing various W956IC gene regions with the Eg101 equivalents. As reported previously, for three of these chimeras, the low early RNA phenotype of Eg101 was restored in BHK cells. Analysis of infections with two of these chimeric viruses in MEFs detected lower early viral RNA levels, higher early viral protein levels, lower early IFN-␤ levels, and higher virus yields similar to those seen after Eg101 infection. The data suggest that replicase protein interactions directly or indirectly regulate genome switching between replication and translation at early times in favor of translation to minimize NF-〉 activation and IFN induction by decreasing the amount of unprotected viral RNA, to produce sufficient viral protein to block canonical type I IFN signaling, and to efficiently remodel cell membranes for exponential genome amplification. West Nile virus (WNV) is a positive-sense, single-stranded RNA, enveloped virus of the family Flaviviridae. The WNV genomic RNA is about 11 kb in length, has a capped 5= end but no poly(A) at the 3= end, and encodes one open reading frame (ORF). The polyprotein precursor produced is posttranslationally processed by virus and host cell proteases to yield three structural proteins, capsid (C), premembrane (prM), and envelope (E), and seven nonstructural (NS) proteins: glycoprotein NS1, membrane anchor NS2A, membrane anchor and protease cofactor NS2B, protease-helicase NS3, membrane anchors NS4A and NS4B, and methyltransferase-RNA-dependent RNA polymerase (RdRp) NS5 (1).The majority of known WNV isolates are classified into two lineages (2-4). Both lineages contain low-and high-virulence strains (5-7). Lineage 1 strains cause epidemics in many parts of the world while lineage 2 strains are endemic to Africa. The lineage II virus 956D117B3 (4, 8) is a laboratory-passaged descendant of the WNV prototype strain B956. Archived 956D117B3 RNA and the 1,496 3= nucleotides (nt) from the lineage 1 strain Eg101 were used to construct the first infectious clone of WNV, SP6WNEg3=/ Xba (also referred to as W956IC) (8). W956IC virus and the parental virus 956D117B3 produce similar growth kinetics and peak titers in both Vero cells and C6/36 cells (8). The full-length W956IC cDNA is stable in bacteria and has been used to efficiently rescue virus with engineered mutations (9, 10). Other studies from our lab have shown that WNV Eg101 and other natural WNV strain infections do not activate eukaryotic translation initiation factor 2-alpha kinase 2 (Eif2ak2, also known as PKR) in BHK cells or mouse embryonic fibro...

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“…Stimulator of interferon genes (STING, also known as MITA, MPYS, and ERIS) is an ER-resident antiviral protein that has traditionally been thought to be a hub signaling adaptor for sensing cytosolic DNA viruses (8)(9)(10)(11)(12). More recently, it was reported that the NS2B3 protease of DENV could specifically cleave human STING in experimental models of DENV infection, thus linking STING to RNA viruses (13,14). However, DENV per se could not trigger the activation of the STING signaling.…”

mentioning

confidence: 99%

Endoplasmic Reticulum Protein SCAP Inhibits Dengue Virus NS2B3 Protease by Suppressing Its K27-Linked Polyubiquitylation

Liu

Zhang

Jin

et al. 2017

J Virol

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Dengue viruses (DENVs) are an emerging threat to global public health. The NS2B3 protease complex of DENV has recently been shown to cleave the antiviral protein STING and thereby subvert the innate immune signaling to facilitate virus replication. Whether host cells have a mechanism to counteract this virus-mediated immunosuppression is unclear. We discovered that the K27-linked polyubiquitination of NS3 protein facilitates its recruitment of NS2B, the formation of NS2B3, and consequently the enhanced cleavage of STING. However, an endoplasmic reticulum (ER) protein, SCAP, through binding to NS2B protein, inhibits the ubiquitination of NS3, rendering NS2B3 protease incapable of binding and cleaving STING. Importantly, ectopic expression of SCAP impaired DENV infection, whereas silencing of SCAP potentiated DENV infection. Collectively, this study uncovered a novel function of SCAP of counteracting the inhibitory action of DENV NS2B3 protease on STING signaling, suggesting that modulation of SCAP levels may have therapeutic implications. IMPORTANCE This study reports the first ubiquitylation target protein in DENV, the NS3 protein, and the unique role of K27-linked polyubiquitylation in NS3's ability to recruit NS2B and formation of the NS2B3 protease complex. Additionally, this study identified novel functions of the ER protein SCAP: one is to compete with NS2B for binding to STING, and the other is to inhibit the ubiquitination of NS3. Both of these functions protect STING from being cleaved by the NS2B3 protease and thus contribute to host antiviral response.

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DENV Inhibits Type I IFN Production in Infected Cells by Cleaving Human STING

Cited by 433 publications

References 55 publications

An Alternative Splicing Isoform of MITA Antagonizes MITA-Mediated Induction of Type I IFNs

An Alternative Splicing Isoform of MITA Antagonizes MITA-Mediated Induction of Type I IFNs

Increased Early RNA Replication by Chimeric West Nile Virus W956IC Leads to IPS-1-Mediated Activation of NF-κB and Insufficient Virus-Mediated Counteraction of the Resulting Canonical Type I Interferon Signaling

Endoplasmic Reticulum Protein SCAP Inhibits Dengue Virus NS2B3 Protease by Suppressing Its K27-Linked Polyubiquitylation

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