Coronavirus papain-like proteases negatively regulate antiviral innate immune response through disruption of STING-mediated signaling.
Viruses have evolved elaborate mechanisms to evade or inactivate the complex system of sensors and signaling molecules that make up the host innate immune response. Here we show that human coronavirus (HCoV) NL63 and severe acute respiratory syndrome (SARS) CoV papain-like proteases (PLP) antagonize...
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Public Library of Science (PLoS)
2012
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oai:doaj.org-article:6ec96f38e90e415097ec935050eb3d822021-11-18T07:29:04ZCoronavirus papain-like proteases negatively regulate antiviral innate immune response through disruption of STING-mediated signaling.1932-620310.1371/journal.pone.0030802https://doaj.org/article/6ec96f38e90e415097ec935050eb3d822012-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/22312431/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203Viruses have evolved elaborate mechanisms to evade or inactivate the complex system of sensors and signaling molecules that make up the host innate immune response. Here we show that human coronavirus (HCoV) NL63 and severe acute respiratory syndrome (SARS) CoV papain-like proteases (PLP) antagonize innate immune signaling mediated by STING (stimulator of interferon genes, also known as MITA/ERIS/MYPS). STING resides in the endoplasmic reticulum and upon activation, forms dimers which assemble with MAVS, TBK-1 and IKKε, leading to IRF-3 activation and subsequent induction of interferon (IFN). We found that expression of the membrane anchored PLP domain from human HCoV-NL63 (PLP2-TM) or SARS-CoV (PLpro-TM) inhibits STING-mediated activation of IRF-3 nuclear translocation and induction of IRF-3 dependent promoters. Both catalytically active and inactive forms of CoV PLPs co-immunoprecipitated with STING, and viral replicase proteins co-localize with STING in HCoV-NL63-infected cells. Ectopic expression of catalytically active PLP2-TM blocks STING dimer formation and negatively regulates assembly of STING-MAVS-TBK1/IKKε complexes required for activation of IRF-3. STING dimerization was also substantially reduced in cells infected with SARS-CoV. Furthermore, the level of ubiquitinated forms of STING, RIG-I, TBK1 and IRF-3 are reduced in cells expressing wild type or catalytic mutants of PLP2-TM, likely contributing to disruption of signaling required for IFN induction. These results describe a new mechanism used by CoVs in which CoV PLPs negatively regulate antiviral defenses by disrupting the STING-mediated IFN induction.Li SunYaling XingXiaojuan ChenYang ZhengYudong YangDaniel B NicholsMark A ClementzBridget S BanachKui LiSusan C BakerZhongbin ChenPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 7, Iss 2, p e30802 (2012) |
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Medicine R Science Q |
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Medicine R Science Q Li Sun Yaling Xing Xiaojuan Chen Yang Zheng Yudong Yang Daniel B Nichols Mark A Clementz Bridget S Banach Kui Li Susan C Baker Zhongbin Chen Coronavirus papain-like proteases negatively regulate antiviral innate immune response through disruption of STING-mediated signaling. |
| description |
Viruses have evolved elaborate mechanisms to evade or inactivate the complex system of sensors and signaling molecules that make up the host innate immune response. Here we show that human coronavirus (HCoV) NL63 and severe acute respiratory syndrome (SARS) CoV papain-like proteases (PLP) antagonize innate immune signaling mediated by STING (stimulator of interferon genes, also known as MITA/ERIS/MYPS). STING resides in the endoplasmic reticulum and upon activation, forms dimers which assemble with MAVS, TBK-1 and IKKε, leading to IRF-3 activation and subsequent induction of interferon (IFN). We found that expression of the membrane anchored PLP domain from human HCoV-NL63 (PLP2-TM) or SARS-CoV (PLpro-TM) inhibits STING-mediated activation of IRF-3 nuclear translocation and induction of IRF-3 dependent promoters. Both catalytically active and inactive forms of CoV PLPs co-immunoprecipitated with STING, and viral replicase proteins co-localize with STING in HCoV-NL63-infected cells. Ectopic expression of catalytically active PLP2-TM blocks STING dimer formation and negatively regulates assembly of STING-MAVS-TBK1/IKKε complexes required for activation of IRF-3. STING dimerization was also substantially reduced in cells infected with SARS-CoV. Furthermore, the level of ubiquitinated forms of STING, RIG-I, TBK1 and IRF-3 are reduced in cells expressing wild type or catalytic mutants of PLP2-TM, likely contributing to disruption of signaling required for IFN induction. These results describe a new mechanism used by CoVs in which CoV PLPs negatively regulate antiviral defenses by disrupting the STING-mediated IFN induction. |
| format |
article |
| author |
Li Sun Yaling Xing Xiaojuan Chen Yang Zheng Yudong Yang Daniel B Nichols Mark A Clementz Bridget S Banach Kui Li Susan C Baker Zhongbin Chen |
| author_facet |
Li Sun Yaling Xing Xiaojuan Chen Yang Zheng Yudong Yang Daniel B Nichols Mark A Clementz Bridget S Banach Kui Li Susan C Baker Zhongbin Chen |
| author_sort |
Li Sun |
| title |
Coronavirus papain-like proteases negatively regulate antiviral innate immune response through disruption of STING-mediated signaling. |
| title_short |
Coronavirus papain-like proteases negatively regulate antiviral innate immune response through disruption of STING-mediated signaling. |
| title_full |
Coronavirus papain-like proteases negatively regulate antiviral innate immune response through disruption of STING-mediated signaling. |
| title_fullStr |
Coronavirus papain-like proteases negatively regulate antiviral innate immune response through disruption of STING-mediated signaling. |
| title_full_unstemmed |
Coronavirus papain-like proteases negatively regulate antiviral innate immune response through disruption of STING-mediated signaling. |
| title_sort |
coronavirus papain-like proteases negatively regulate antiviral innate immune response through disruption of sting-mediated signaling. |
| publisher |
Public Library of Science (PLoS) |
| publishDate |
2012 |
| url |
https://doaj.org/article/6ec96f38e90e415097ec935050eb3d82 |
| work_keys_str_mv |
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