The Reovirus Σ3 Protein Inhibits NF-κB-Dependent Antiviral Signaling
Journal of virology(2022)
Abstract
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 hosts’ 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. IMPORTANCE Host cells mount a response to curb virus replication in infected cells and prevent spread of virus to neighboring, as yet uninfected cells. The NF-κB family of proteins is important for the cell to mediate this response. In this study, we show that a single protein, σ3, produced by mammalian reovirus, impairs the function of NF-κB. We demonstrate that by blocking NF-κB, σ3 diminishes the hosts’ response to infection and promotes viral replication. This work identifies a second, previously unknown mechanism by which reovirus blocks this aspect of the host cell response. ### Competing Interest Statement The authors have declared no competing interest.
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