Pseudorabies virus infection triggers pUL46-mediated phosphorylation of connexin-43 and closure of gap junctions to promote intercellular virus spread.
Gap junctions (GJs) play a pivotal role in intercellular communication between eukaryotic cells, including transfer of biomolecules that contribute to the innate and adaptive immune response. However, if, how and why viruses affect gap junction intercellular communication (GJIC) remains largely unex...
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2025-01-01
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| Series: | PLoS Pathogens |
| Online Access: | https://doi.org/10.1371/journal.ppat.1012895 |
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| _version_ | 1832540327314980864 |
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| author | Alexander Tishchenko Nicolás Romero Cliff Van Waesberghe Jonas L Delva Oliver Vickman Gregory A Smith Thomas C Mettenleiter Walter Fuchs Barbara G Klupp Herman W Favoreel |
| author_facet | Alexander Tishchenko Nicolás Romero Cliff Van Waesberghe Jonas L Delva Oliver Vickman Gregory A Smith Thomas C Mettenleiter Walter Fuchs Barbara G Klupp Herman W Favoreel |
| author_sort | Alexander Tishchenko |
| collection | DOAJ |
| description | Gap junctions (GJs) play a pivotal role in intercellular communication between eukaryotic cells, including transfer of biomolecules that contribute to the innate and adaptive immune response. However, if, how and why viruses affect gap junction intercellular communication (GJIC) remains largely unexplored. Here, we describe how the alphaherpesvirus pseudorabies virus (PRV) triggers ERK1/2-mediated phosphorylation of the main gap junction component connexin 43 (Cx43) and closure of GJIC, which depends on the viral protein pUL46. Consequently, a UL46null PRV mutant is unable to phosphorylate Cx43 or inhibit GJIC and displays reduced intercellular spread, which is effectively rescued by pharmacological inhibition of GJIC. Intercellular spread of UL46null PRV is also rescued by inhibition of the stimulator of interferon genes (STING), suggesting that pUL46-mediated suppression of GJIC contributes to intercellular virus spread by hindering intercellular communication that activates STING. The current study identifies key viral and cellular proteins involved in alphaherpesvirus-mediated suppression of GJIC and reveals that GJIC inhibition enhances virus intercellular spread, thereby opening new avenues for the design of targeted antiviral therapies. |
| format | Article |
| id | doaj-art-6fb6c40e487d456c8f2490ccbb3bc11b |
| institution | Kabale University |
| issn | 1553-7366 1553-7374 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Pathogens |
| spelling | doaj-art-6fb6c40e487d456c8f2490ccbb3bc11b2025-02-05T05:30:53ZengPublic Library of Science (PLoS)PLoS Pathogens1553-73661553-73742025-01-01211e101289510.1371/journal.ppat.1012895Pseudorabies virus infection triggers pUL46-mediated phosphorylation of connexin-43 and closure of gap junctions to promote intercellular virus spread.Alexander TishchenkoNicolás RomeroCliff Van WaesbergheJonas L DelvaOliver VickmanGregory A SmithThomas C MettenleiterWalter FuchsBarbara G KluppHerman W FavoreelGap junctions (GJs) play a pivotal role in intercellular communication between eukaryotic cells, including transfer of biomolecules that contribute to the innate and adaptive immune response. However, if, how and why viruses affect gap junction intercellular communication (GJIC) remains largely unexplored. Here, we describe how the alphaherpesvirus pseudorabies virus (PRV) triggers ERK1/2-mediated phosphorylation of the main gap junction component connexin 43 (Cx43) and closure of GJIC, which depends on the viral protein pUL46. Consequently, a UL46null PRV mutant is unable to phosphorylate Cx43 or inhibit GJIC and displays reduced intercellular spread, which is effectively rescued by pharmacological inhibition of GJIC. Intercellular spread of UL46null PRV is also rescued by inhibition of the stimulator of interferon genes (STING), suggesting that pUL46-mediated suppression of GJIC contributes to intercellular virus spread by hindering intercellular communication that activates STING. The current study identifies key viral and cellular proteins involved in alphaherpesvirus-mediated suppression of GJIC and reveals that GJIC inhibition enhances virus intercellular spread, thereby opening new avenues for the design of targeted antiviral therapies.https://doi.org/10.1371/journal.ppat.1012895 |
| spellingShingle | Alexander Tishchenko Nicolás Romero Cliff Van Waesberghe Jonas L Delva Oliver Vickman Gregory A Smith Thomas C Mettenleiter Walter Fuchs Barbara G Klupp Herman W Favoreel Pseudorabies virus infection triggers pUL46-mediated phosphorylation of connexin-43 and closure of gap junctions to promote intercellular virus spread. PLoS Pathogens |
| title | Pseudorabies virus infection triggers pUL46-mediated phosphorylation of connexin-43 and closure of gap junctions to promote intercellular virus spread. |
| title_full | Pseudorabies virus infection triggers pUL46-mediated phosphorylation of connexin-43 and closure of gap junctions to promote intercellular virus spread. |
| title_fullStr | Pseudorabies virus infection triggers pUL46-mediated phosphorylation of connexin-43 and closure of gap junctions to promote intercellular virus spread. |
| title_full_unstemmed | Pseudorabies virus infection triggers pUL46-mediated phosphorylation of connexin-43 and closure of gap junctions to promote intercellular virus spread. |
| title_short | Pseudorabies virus infection triggers pUL46-mediated phosphorylation of connexin-43 and closure of gap junctions to promote intercellular virus spread. |
| title_sort | pseudorabies virus infection triggers pul46 mediated phosphorylation of connexin 43 and closure of gap junctions to promote intercellular virus spread |
| url | https://doi.org/10.1371/journal.ppat.1012895 |
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