Loss of IKK subunits limits NF-κB signaling in reovirus infected cells

McNamara, Andrew J.; Danthi, Pranav

doi:10.1101/843680

Cited by 3 publications

(12 citation statements)

References 47 publications

(57 reference statements)

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“…2). Thus, σ3 inhibits NF-κB via a different mechanism than what has been described previously (13). We found that σ3 inhibits the expression of some but not all NF-κB target genes (Fig.…”

Section: Discussionsupporting

confidence: 55%

“…Sensing of reovirus genomic RNA by RLRs leads to the activation of IRF3 and NF-κB, which lead to the production of interferon (IFN) and other inflammatory cytokines (9)(10)(11)(12). (13). Consistent with this, the genetic absence of either IRF3 or NF-κB exacerbates reovirus disease in a newborn mouse model (14,15).…”

Section: Introductionmentioning

confidence: 86%

“…NF-κB activity is observed in reovirus infected cells at early stages of infection (16)(17)(18). Later following infection, NF-κBdependent gene expression is no longer active despite the continued presence of viral RNA within the cytoplasm (13,17). At this stage, addition of exogenous NF-κB agonists such as Tumor Necrosis Factor alpha (TNFα) also fails to stimulate NF-κB, indicating that the function of a signaling component common to both RLR and TNFα signaling is compromised (13,17).…”

Section: Introductionmentioning

confidence: 99%

“…Later following infection, NF-κBdependent gene expression is no longer active despite the continued presence of viral RNA within the cytoplasm (13,17). At this stage, addition of exogenous NF-κB agonists such as Tumor Necrosis Factor alpha (TNFα) also fails to stimulate NF-κB, indicating that the function of a signaling component common to both RLR and TNFα signaling is compromised (13,17). Inhibition of NF-κB occurs through the loss of two components of the IKK complex, IKKβ and NEMO, The loss of IKKβ and NEMO is dependent on viral gene expression (13).…”

Section: Introductionmentioning

confidence: 99%

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The reovirus σ3 protein inhibits NF-κB-dependent antiviral signaling

McNamara

Brooks

Danthi

2021

Preprint

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Viral antagonism of innate immune pathways is a common mechanism by which viruses evade immune surveillance. Infection of host cells with reovirus leads to the blockade of NF-κB, a key transcriptional regulator of the host's innate immune response. One mechanism by which reovirus infection results in inhibition of NF-κB is through a diminishment in levels of upstream activators, IKKβ and NEMO. Here, we demonstrate a second, distinct mechanism by which reovirus blocks NF-κB. We report that expression of a single viral protein, σ3, is sufficient to inhibit expression of NF-κB target genes. Further, σ3-mediated blockade of NF-κB occurs without changes to IKK levels or activity. Expression of only a subset of NF-κB target genes is reduced. Among NF-κB targets, the expression of type I interferon is significantly diminished by σ3 expression. Correspondingly, ectopic expression of σ3 enhances viral replication. Expression of NF-κB target genes varies following infection with closely related reovirus strains. Our genetic analysis identifies that these differences are controlled by polymorphisms in the amino acid sequence of σ3. This work identifies a new role for reovirus σ3 as a viral antagonist of the NF-κB-dependent antiviral pathways.

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Section: Discussionsupporting

confidence: 55%

Section: Introductionmentioning

confidence: 86%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The reovirus σ3 protein inhibits NF-κB-dependent antiviral signaling

McNamara

Brooks

Danthi

2021

Preprint

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“…Antiviral cytokines are also under control of nuclear factor kappa B (NF-kB), a family of transcription factors. It has been suggested that NF-kB is rendered inactive because virus infection results in reduced levels of inhibitor of kappa B kinase (IKK) complex, which is needed for NF-kB function ( 35 ). The canonical complex of IKK is composed of IKKα/IKKβ/IKKγ.…”

Section: Resultsmentioning

confidence: 99%

Bovine Delta Papillomavirus E5 Oncoprotein Interacts With TRIM25 and Hampers Antiviral Innate Immune Response Mediated by RIG-I-Like Receptors

et al. 2021

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Persistent infection and tumourigenesis by papillomaviruses (PVs) require viral manipulation of various of cellular processes, including those involved in innate immune responses. Herein, we showed that bovine PV (BPV) E5 oncoprotein interacts with a tripartite motif-containing 25 (TRIM25) but not with Riplet in spontaneous BPV infection of urothelial cells of cattle. Statistically significant reduced protein levels of TRIM25, retinoic acid-inducible gene I (RIG-I), and melanoma differentiation-associated gene 5 (MDA5) were detected by Western blot analysis. Real-time quantitative PCR revealed marked transcriptional downregulation of RIG-I and MDA5 in E5-expressing cells compared with healthy urothelial cells. Mitochondrial antiviral signalling (MAVS) protein expression did not vary significantly between diseased and healthy cells. Co-immunoprecipitation studies showed that MAVS interacted with a protein network composed of Sec13, which is a positive regulator of MAVS-mediated RLR antiviral signalling, phosphorylated TANK binding kinase 1 (TBK1), and phosphorylated interferon regulatory factor 3 (IRF3). Immunoblotting revealed significantly low expression levels of Sec13 in BPV-infected cells. Low levels of Sec13 resulted in a weaker host antiviral immune response, as it attenuates MAVS-mediated IRF3 activation. Furthermore, western blot analysis revealed significantly reduced expression levels of pTBK1, which plays an essential role in the activation and phosphorylation of IRF3, a prerequisite for the latter to enter the nucleus to activate type 1 IFN genes. Our results suggested that the innate immune signalling pathway mediated by RIG-I-like receptors (RLRs) was impaired in cells infected with BPVs. Therefore, an effective immune response is not elicited against these viruses, which facilitates persistent viral infection.

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