Viral suppression of the interferon system

Weber, Friedemann; Haller, Otto

doi:10.1016/j.biochi.2007.01.005

Cited by 67 publications

(62 citation statements)

References 138 publications

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“…Be that as it may, with at least two KSHV proteins devoted to inhibition of IFN signaling and four proteins that can antagonize IFN induction or amplification, it is clear that KSHV evolution has selected very strongly for abrogation of IFN action, implying a key role for IFN in the control of this herpesvirus from early in its evolutionary history. This redundancy is an extreme example of a phenomenon that has been seen in other viral systems, many of which devote several viral genes to nullification of IFN induction or action (16,44,45).…”

Section: Discussionmentioning

confidence: 92%

A Kaposi's Sarcoma-Associated Herpesvirus Protein That Forms Inhibitory Complexes with Type I Interferon Receptor Subunits, Jak and STAT Proteins, and Blocks Interferon-Mediated Signal Transduction

Bisson

Page

Ganem

2009

J Virol

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Type I interferons (IFNs) are important mediators of innate antiviral defense and function by activating a signaling pathway through their cognate type I receptor (IFNAR). Here we report that lytic replication of Kaposi's sarcoma-associated herpesvirus (KSHV) efficiently blocks type I IFN signaling and that an important effector of this blockade is the viral protein RIF, the product of open reading frame 10. RIF blocks IFN signaling by formation of inhibitory complexes that contain IFNAR subunits, the Janus kinases Jak1 and Tyk2, and the STAT2 transcription factor. Activation of both Tyk2 and Jak1 is inhibited, and abnormal recruitment of STAT2 to IFNAR1 occurs despite the decrement in Tyk2 activity. As a result of these actions, phosphorylation of both STAT2 and STAT1 is impaired, with subsequent failure of ISGF3 accumulation in the nucleus. The presence in the viral genome of potent inhibitors of type I IFN signaling, along with several viral genes that block IFN induction, highlights the importance of the IFN pathway in the control of this human tumor virus infection.The earliest host defenses mobilized against viral infection are those of the innate immune system. These include a variety of cellular elements and humoral factors; chief among the latter are the type 1 interferons (IFNs), IFN-␣ and IFN-␤. Expression of these cytokines is rapidly induced in infected cells, from which they are efficiently exported into the surrounding microenvironment. There, they engage a single heterodimeric receptor, IFNAR, and trigger activation of a signaling pathway that generates a plethora of proteins with broad-spectrum antiviral activities. The importance of this pathway in antiviral defense is attested to by the fact that mice bearing genetic lesions in IFNAR subunits (or one or more of their downstream effectors) are more susceptible to a variety of experimental viral infections, including picornaviruses, influenza viruses, rotaviruses, alphaviruses, bunyaviruses, herpesviruses, and retroviruses (2,3,14,18,31,39,42,43).The IFN signaling pathway is elicited by interaction of type I IFN with its receptor, a heterodimer composed of two subunits, IFNAR1 and IFNAR2. In the ground state, IFNAR1 is associated with the Janus kinase Tyk2 and IFNAR2 with the Janus kinase Jak1. IFN binding is thought to bring the IFNAR subunits together, thereby facilitating cross-tyrosine phosphorylation and activation of the two Janus kinases. Activated Tyk2 can then phosphorylate tyrosine 466 (Y466) and other sites on IFNAR1, an event that is important for subsequent signaling.The IFNAR2 cytosolic domains are preassociated with the STAT (signal transducer and activator of transcription) proteins, STAT1 and STAT2. Following receptor engagement by IFN, STAT2 is transferred to IFNAR1 by interaction of phosphorylated Y466 with the STAT2 SH2 domain. Subsequent to this, both STAT proteins are phosphorylated at specific tyrosine residues, which allows the two proteins to form a STAT1/2 heterodimer based on SH2/phosphotyrosine interactions. This hete...

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Section: Discussionmentioning

confidence: 92%

A Kaposi's Sarcoma-Associated Herpesvirus Protein That Forms Inhibitory Complexes with Type I Interferon Receptor Subunits, Jak and STAT Proteins, and Blocks Interferon-Mediated Signal Transduction

Bisson

Page

Ganem

2009

J Virol

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“…These results clearly indicate that DENV blocks or does not induce the IFN pathway in infected cells. Several viruses, including some flaviviruses, have been reported to block IFN production in infected cells as an efficient immune evasion mechanism by interfering with the pathway at different levels (4,9,51). However, there is still little evidence about how DENV could be interrupting this pathway.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of the Type I Interferon Response in Human Dendritic Cells by Dengue Virus Infection Requires a Catalytically Active NS2B3 Complex

Rodríguez-Madoz

Belicha-Villanueva

Bernal-Rubio

et al. 2010

J Virol

127

123

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Dengue virus (DENV) is the most prevalent arthropod-borne human virus, able to infect and replicate in human dendritic cells (DCs), inducing their activation and the production of proinflammatory cytokines. However, DENV can successfully evade the immune response in order to produce disease in humans. Several mechanisms of immune evasion have been suggested for DENV, most of them involving interference with type I interferon (IFN) signaling. We recently reported that DENV infection of human DCs does not induce type I IFN production by those infected DCs, impairing their ability to prime naive T cells toward Th1 immunity. In this article, we report that DENV also reduces the ability of DCs to produce type I IFN in response to several inducers, such as infection with other viruses or exposure to Toll-like receptor (TLR) ligands, indicating that DENV antagonizes the type I IFN production pathway in human DCs. DENV-infected human DCs showed a reduced type I IFN response to Newcastle disease virus (NDV), Sendai virus (SeV), and Semliki Forest virus (SFV) infection and to the TLR3 agonist poly(I:C). This inhibitory effect is DENV dose dependent, requires DENV replication, and takes place in DENV-infected DCs as early as 2 h after infection. Expressing individual proteins of DENV in the presence of an IFN-␣/␤ production inducer reveals that a catalytically active viral protease complex is required to reduce type I IFN production significantly. These results provide a new mechanism by which DENV evades the immune system in humans.Dengue virus (DENV), a member of the Flaviviridae family and grouped within the Flavivirus genus (27), is the most prevalent arthropod-borne human virus with significant medical and biodefense importance (8,27). DENV is transmitted by mosquitoes, usually Aedes aegypti, with an estimated 100 million cases per year and 2.5 billion people at risk (53). Clinical manifestations include dengue fever, a febrile illness with rash, and dengue hemorrhagic fever, a severe and often lethal illness (53). There are four DENV serotypes (DENV1 to -4), and infection with one serotype confers life-long protection against that serotype at least by the induction of neutralizing antibodies (17). Currently there is no vaccine or effective antiviral treatment against this virus, and the most effective protective measures involve mosquito control.The DENV genome is a positive-strand RNA molecule of about 11 kb in length, with one single open reading frame (ORF) flanked by 5Ј and 3Ј nontranslated regions (27). After viral infection and the release of the viral nucleocapsid into the cytosol, a 3,391-amino-acid (aa)-long polyprotein is translated from the viral RNA at the surface of the endoplasmic reticulum (ER) (27). This polyprotein is cleaved into three structural (C, prM, and E) and seven nonstructural (NS1, NS2A, NS2B, NS3, NS4A, NS4B, and NS5) proteins due to the combined and coordinated activities of host cell proteases in the ER and the viral protease complex (NS2B3) in the cytoplasm (27). The viral protease cle...

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“…Thus, NSs is different from most other viral IFN antagonists (15,55) by acting downstream of the canonical RIG-I/IRF-3 signaling pathway.…”

Section: Discussionmentioning

confidence: 96%

Interferon Antagonist NSs of La Crosse Virus Triggers a DNA Damage Response-like Degradation of Transcribing RNA Polymerase II

Verbruggen

Ruf

Blakqori

et al. 2011

Journal of Biological Chemistry

Self Cite

107

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La Crosse encephalitis virus (LACV) is a mosquito-borne member of the negative-strand RNA virus family Bunyaviridae. We have previously shown that the virulence factor NSs of LACV is an efficient inhibitor of the antiviral type I interferon system. A recombinant virus unable to express NSs (rLACVdelNSs) strongly induced interferon transcription, whereas the corresponding wt virus (rLACV) suppressed it. Here, we show that interferon induction by rLACVdelNSs mainly occurs through the signaling pathway leading from the pattern recognition receptor RIG-I to the transcription factor IRF-3. NSs expressed by rLACV, however, acts downstream of IRF-3 by specifically blocking RNA polymerase II-dependent transcription. Further investigations revealed that NSs induces proteasomal degradation of the mammalian RNA polymerase II subunit RPB1. NSs thereby selectively targets RPB1 molecules of elongating RNA polymerase II complexes, the so-called IIo form. This phenotype has similarities to the cellular DNA damage response, and NSs was indeed found to transactivate the DNA damage response gene pak6. Moreover, NSs expressed by rLACV boosted serine 139 phosphorylation of histone H2A.X, one of the earliest cellular reactions to damaged DNA. However, other DNA damage response markers such as up-regulation and serine 15 phosphorylation of p53 or serine 1524 phosphorylation of BRCA1 were not triggered by LACV infection. Collectively, our data indicate that the strong suppression of interferon induction by LACV NSs is based on a shutdown of RNA polymerase II transcription and that NSs achieves this by exploiting parts of the cellular DNA damage response pathway to degrade IIo-borne RPB1 subunits. La Crosse virus (LACV)3 is a mosquito-borne member of the family Bunyaviridae, genus Orthobunyavirus. LACV infections are an important cause of severe encephalitis and meningitis in children and young adults in the Western United States (1-3). Around 75-100 cases per year require hospitalizations (4), and more than 10% of those patients will have long-lasting neurological deficits (1, 5). Recent observations suggest that the virus is spreading to new geographic regions (6).Like other arboviruses, LACV cycles between vertebrate and invertebrate hosts, being able to replicate both in mammals and in insects. Depending on the host, however, the outcome of infection is different (7). In mammalian cells, infection is lytic and causes host cell shutoff and cell death. In insect cells infection is non-cytolytic and leads to long term viral persistence.LACV is enveloped and has a tri-segmented singlestranded RNA genome of negative-sense polarity. Transcription and replication of the genome occur in the cytoplasm, and particles bud into the Golgi apparatus before being secreted. The viral genome encodes four structural proteins, the viral polymerase (L) on the large (L) segment, two glycoproteins (Gn and Gc) on the medium (M) segment, and the viral nucleocapsid protein (N) on the smallest (S) segment. In addition, LACV expresses two nonstructural protei...

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Viral suppression of the interferon system

Cited by 67 publications

References 138 publications

A Kaposi's Sarcoma-Associated Herpesvirus Protein That Forms Inhibitory Complexes with Type I Interferon Receptor Subunits, Jak and STAT Proteins, and Blocks Interferon-Mediated Signal Transduction

A Kaposi's Sarcoma-Associated Herpesvirus Protein That Forms Inhibitory Complexes with Type I Interferon Receptor Subunits, Jak and STAT Proteins, and Blocks Interferon-Mediated Signal Transduction

Inhibition of the Type I Interferon Response in Human Dendritic Cells by Dengue Virus Infection Requires a Catalytically Active NS2B3 Complex

Interferon Antagonist NSs of La Crosse Virus Triggers a DNA Damage Response-like Degradation of Transcribing RNA Polymerase II

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