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Coronavirus papain-like proteases negatively regulate antiviral innate immune response through disruption of STING-mediated signaling.
PLoS One. 2012; 7(2):e30802.Plos

Abstract

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.

Authors+Show Affiliations

Division of Infection and Immunity, Department of Electromagnetic and Laser Biology, Beijing Institute of Radiation Medicine, Beijing, China.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

Language

eng

PubMed ID

22312431

Citation

Sun, Li, et al. "Coronavirus Papain-like Proteases Negatively Regulate Antiviral Innate Immune Response Through Disruption of STING-mediated Signaling." PloS One, vol. 7, no. 2, 2012, pp. e30802.
Sun L, Xing Y, Chen X, et al. Coronavirus papain-like proteases negatively regulate antiviral innate immune response through disruption of STING-mediated signaling. PLoS ONE. 2012;7(2):e30802.
Sun, L., Xing, Y., Chen, X., Zheng, Y., Yang, Y., Nichols, D. B., Clementz, M. A., Banach, B. S., Li, K., Baker, S. C., & Chen, Z. (2012). Coronavirus papain-like proteases negatively regulate antiviral innate immune response through disruption of STING-mediated signaling. PloS One, 7(2), e30802. https://doi.org/10.1371/journal.pone.0030802
Sun L, et al. Coronavirus Papain-like Proteases Negatively Regulate Antiviral Innate Immune Response Through Disruption of STING-mediated Signaling. PLoS ONE. 2012;7(2):e30802. PubMed PMID: 22312431.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Coronavirus papain-like proteases negatively regulate antiviral innate immune response through disruption of STING-mediated signaling. AU - Sun,Li, AU - Xing,Yaling, AU - Chen,Xiaojuan, AU - Zheng,Yang, AU - Yang,Yudong, AU - Nichols,Daniel B, AU - Clementz,Mark A, AU - Banach,Bridget S, AU - Li,Kui, AU - Baker,Susan C, AU - Chen,Zhongbin, Y1 - 2012/02/01/ PY - 2011/11/11/received PY - 2011/12/21/accepted PY - 2012/2/8/entrez PY - 2012/2/9/pubmed PY - 2012/6/15/medline SP - e30802 EP - e30802 JF - PloS one JO - PLoS ONE VL - 7 IS - 2 N2 - 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. SN - 1932-6203 UR - https://www.unboundmedicine.com/medline/citation/22312431/Coronavirus_papain_like_proteases_negatively_regulate_antiviral_innate_immune_response_through_disruption_of_STING_mediated_signaling_ L2 - https://dx.plos.org/10.1371/journal.pone.0030802 DB - PRIME DP - Unbound Medicine ER -