Abstract
The transcription factors IRF3 and NF-κB are crucial in innate immune signalling in response to many viral and bacterial pathogens. However, mechanisms leading to their activation remain incompletely understood. Viral RNA can be detected by RLR receptors, such as RIG-I and MDA5, and the dsRNA receptor TLR3. Alternatively, the DExD-Box RNA helicases DDX1-DDX21-DHX36 activate IRF3/NF-κB in a TRIF-dependent manner independent of RIG-I, MDA5, or TLR3. Here, we describe DDX50, which shares 55.6% amino acid identity with DDX21, as a non-redundant factor that promotes activation of the IRF3 signalling pathway following its stimulation with viral RNA or infection with RNA and DNA viruses. Deletion of DDX50 in mouse and human cells impaired IRF3 phosphorylation and IRF3-dependent endogenous gene expression and cytokine/chemokine production in response to cytoplasmic dsRNA (polyIC transfection), and infection by RNA and DNA viruses. Mechanistically, whilst DDX50 co-immunoprecipitated TRIF, it acted independently to the previously described TRIF-dependent RNA sensor DDX1. Indeed, shRNA-mediated depletion of DDX1 showed DDX1 was dispensable for signalling in response to RNA virus infection. Importantly, loss of DDX50 resulted in a significant increase in replication and dissemination of virus following infection with vaccinia virus, herpes simplex virus, or Zika virus, highlighting its important role as a broad-ranging viral restriction factor.
Highlights
Interferon (IFN) regulatory factor 3 (IRF3)-dependent signalling is crucial for pathogen clearance and host survival in response to infection by many viral and bacterial pathogens [1,2].IRF3 signalling is tightly regulated and is triggered by intracellular cytoplasmic/endoplasmic detection of viral RNA [3] and DNA by pattern recognition receptors (PRRs) [4]
vaccinia virus (VACV), resulting in significantly lower viral titres (Figure S4B). This suggests that DDX50 restricts plaque formation when cells are infected at low MOI and without DDX50, a greater proportion of virus particles entering cells escape host defences and establish a plaque. These results provide evidence that DDX50 promotes antiviral signalling during infection and is a restriction factor for both DNA and RNA viruses, with its loss resulting in increased viral spread and subsequent replication in tissue culture
Zhang and colleagues described a TLR3, retinoic acid-inducible gene I (RIG-I), and MDA5-independent pathway in mouse dendritic cells in which cytoplasmic RNA was sensed by a complex consisting of DDX1-DDX21-DHX36, leading to recruitment of TRIF [17]
Summary
Interferon (IFN) regulatory factor 3 (IRF3)-dependent signalling is crucial for pathogen clearance and host survival in response to infection by many viral and bacterial pathogens [1,2].IRF3 signalling is tightly regulated and is triggered by intracellular cytoplasmic/endoplasmic detection of viral RNA (dsRNA/50 -ppp/pp-RNA) [3] and DNA by pattern recognition receptors (PRRs) [4]. Interferon (IFN) regulatory factor 3 (IRF3)-dependent signalling is crucial for pathogen clearance and host survival in response to infection by many viral and bacterial pathogens [1,2]. RIG-I/MDA5 activation leads to mitochondrial antiviral signalling protein (MAVS)-dependent autophosphorylation of TANKbinding protein-1 (TBK1). IRF3 and NF-κB transcriptionally upregulate the expression of IFNs, inflammatory cytokines, and chemokines, including IFNβ and C-X-C motif chemokine 10 (CXCL10/IP-10), and IRF3-dependent viral restriction factors [8,9]. These events establish the host antiviral innate immune response, restricting viral replication and aiding clearance of infection
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