DDX50 Is a Viral Restriction Factor That Enhances IRF3 Activation
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 recept...
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| Format: | Article |
| Language: | English |
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MDPI AG
2022-02-01
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| Series: | Viruses |
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| Online Access: | https://www.mdpi.com/1999-4915/14/2/316 |
| _version_ | 1797475994372669440 |
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| author | Mitchell A. Pallett Yongxu Lu Geoffrey L. Smith |
| author_facet | Mitchell A. Pallett Yongxu Lu Geoffrey L. Smith |
| author_sort | Mitchell A. Pallett |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-09T20:52:36Z |
| format | Article |
| id | doaj.art-6fdf15c1903c4a93955b71bc04dc98bb |
| institution | Directory Open Access Journal |
| issn | 1999-4915 |
| language | English |
| last_indexed | 2024-03-09T20:52:36Z |
| publishDate | 2022-02-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Viruses |
| spelling | doaj.art-6fdf15c1903c4a93955b71bc04dc98bb2023-11-23T22:30:57ZengMDPI AGViruses1999-49152022-02-0114231610.3390/v14020316DDX50 Is a Viral Restriction Factor That Enhances IRF3 ActivationMitchell A. Pallett0Yongxu Lu1Geoffrey L. Smith2Department of Pathology, University of Cambridge, Tennis Court Road, Cambridge CB2 1QP, UKDepartment of Pathology, University of Cambridge, Tennis Court Road, Cambridge CB2 1QP, UKDepartment of Pathology, University of Cambridge, Tennis Court Road, Cambridge CB2 1QP, UKThe 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.https://www.mdpi.com/1999-4915/14/2/316IRF3antiviralDExD-box helicaseRLRZikaHSV |
| spellingShingle | Mitchell A. Pallett Yongxu Lu Geoffrey L. Smith DDX50 Is a Viral Restriction Factor That Enhances IRF3 Activation Viruses IRF3 antiviral DExD-box helicase RLR Zika HSV |
| title | DDX50 Is a Viral Restriction Factor That Enhances IRF3 Activation |
| title_full | DDX50 Is a Viral Restriction Factor That Enhances IRF3 Activation |
| title_fullStr | DDX50 Is a Viral Restriction Factor That Enhances IRF3 Activation |
| title_full_unstemmed | DDX50 Is a Viral Restriction Factor That Enhances IRF3 Activation |
| title_short | DDX50 Is a Viral Restriction Factor That Enhances IRF3 Activation |
| title_sort | ddx50 is a viral restriction factor that enhances irf3 activation |
| topic | IRF3 antiviral DExD-box helicase RLR Zika HSV |
| url | https://www.mdpi.com/1999-4915/14/2/316 |
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