PCV2 targets cGAS to inhibit type I interferon induction to promote other DNA virus infection.
Viruses use diverse strategies to impair the antiviral immunity of host in order to promote infection and pathogenesis. Herein, we found that PCV2 infection promotes the infection of DNA viruses through inhibiting IFN-β induction in vivo and in vitro. In the early phase of infection, PCV2 promotes t...
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2021
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oai:doaj.org-article:2d35ee003edf41508e1ef81301f9b5f72021-12-02T20:00:08ZPCV2 targets cGAS to inhibit type I interferon induction to promote other DNA virus infection.1553-73661553-737410.1371/journal.ppat.1009940https://doaj.org/article/2d35ee003edf41508e1ef81301f9b5f72021-09-01T00:00:00Zhttps://doi.org/10.1371/journal.ppat.1009940https://doaj.org/toc/1553-7366https://doaj.org/toc/1553-7374Viruses use diverse strategies to impair the antiviral immunity of host in order to promote infection and pathogenesis. Herein, we found that PCV2 infection promotes the infection of DNA viruses through inhibiting IFN-β induction in vivo and in vitro. In the early phase of infection, PCV2 promotes the phosphorylation of cGAS at S278 via activation of PI3K/Akt signaling, which directly silences the catalytic activity of cGAS. Subsequently, phosphorylation of cGAS at S278 can facilitate the K48-linked poly-ubiquitination of cGAS at K389, which can been served as a signal for recognizing by the ubiquitin-binding domain of histone deacetylase 6 (HDAC6), to promote the translocation of K48-ubiquitinated-cGAS from cytosol to autolysosome depending on the deacetylase activity of HDAC6, thereby eventually resulting in a markedly increased cGAS degradation in PCV2 infection-induced autophagic cells relative to Earle's Balanced Salt Solution (EBSS)-induced autophagic cells (a typical starving autophagy). Importantly, we found that PCV2 Cap and its binding protein gC1qR act as predominant regulators to promote porcine cGAS phosphorylation and HDAC6 activation through mediating PI3K/AKT signaling and PKCδ signaling activation. Based on this finding, gC1qR-binding activity deficient PCV2 mutant (PCV2RmA) indeed shows a weakened inhibitory effect on IFN-β induction and a weaker boost effect for other DNA viruses infection compared to wild-type PCV2. Collectively, our findings illuminate a systematic regulation mechanism by which porcine circovirus counteracts the cGAS-STING signaling pathway to inhibit the type I interferon induction and promote DNA virus infection, and identify gC1qR as an important regulator for the immunosuppression induced by PCV2.Zhenyu WangJing ChenXingchen WuDan MaXiaohua ZhangRuizhen LiCong HanHaixin LiuXiangrui YinQian DuDewen TongYong HuangPublic Library of Science (PLoS)articleImmunologic diseases. AllergyRC581-607Biology (General)QH301-705.5ENPLoS Pathogens, Vol 17, Iss 9, p e1009940 (2021) |
| institution |
DOAJ |
| collection |
DOAJ |
| language |
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| topic |
Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5 |
| spellingShingle |
Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5 Zhenyu Wang Jing Chen Xingchen Wu Dan Ma Xiaohua Zhang Ruizhen Li Cong Han Haixin Liu Xiangrui Yin Qian Du Dewen Tong Yong Huang PCV2 targets cGAS to inhibit type I interferon induction to promote other DNA virus infection. |
| description |
Viruses use diverse strategies to impair the antiviral immunity of host in order to promote infection and pathogenesis. Herein, we found that PCV2 infection promotes the infection of DNA viruses through inhibiting IFN-β induction in vivo and in vitro. In the early phase of infection, PCV2 promotes the phosphorylation of cGAS at S278 via activation of PI3K/Akt signaling, which directly silences the catalytic activity of cGAS. Subsequently, phosphorylation of cGAS at S278 can facilitate the K48-linked poly-ubiquitination of cGAS at K389, which can been served as a signal for recognizing by the ubiquitin-binding domain of histone deacetylase 6 (HDAC6), to promote the translocation of K48-ubiquitinated-cGAS from cytosol to autolysosome depending on the deacetylase activity of HDAC6, thereby eventually resulting in a markedly increased cGAS degradation in PCV2 infection-induced autophagic cells relative to Earle's Balanced Salt Solution (EBSS)-induced autophagic cells (a typical starving autophagy). Importantly, we found that PCV2 Cap and its binding protein gC1qR act as predominant regulators to promote porcine cGAS phosphorylation and HDAC6 activation through mediating PI3K/AKT signaling and PKCδ signaling activation. Based on this finding, gC1qR-binding activity deficient PCV2 mutant (PCV2RmA) indeed shows a weakened inhibitory effect on IFN-β induction and a weaker boost effect for other DNA viruses infection compared to wild-type PCV2. Collectively, our findings illuminate a systematic regulation mechanism by which porcine circovirus counteracts the cGAS-STING signaling pathway to inhibit the type I interferon induction and promote DNA virus infection, and identify gC1qR as an important regulator for the immunosuppression induced by PCV2. |
| format |
article |
| author |
Zhenyu Wang Jing Chen Xingchen Wu Dan Ma Xiaohua Zhang Ruizhen Li Cong Han Haixin Liu Xiangrui Yin Qian Du Dewen Tong Yong Huang |
| author_facet |
Zhenyu Wang Jing Chen Xingchen Wu Dan Ma Xiaohua Zhang Ruizhen Li Cong Han Haixin Liu Xiangrui Yin Qian Du Dewen Tong Yong Huang |
| author_sort |
Zhenyu Wang |
| title |
PCV2 targets cGAS to inhibit type I interferon induction to promote other DNA virus infection. |
| title_short |
PCV2 targets cGAS to inhibit type I interferon induction to promote other DNA virus infection. |
| title_full |
PCV2 targets cGAS to inhibit type I interferon induction to promote other DNA virus infection. |
| title_fullStr |
PCV2 targets cGAS to inhibit type I interferon induction to promote other DNA virus infection. |
| title_full_unstemmed |
PCV2 targets cGAS to inhibit type I interferon induction to promote other DNA virus infection. |
| title_sort |
pcv2 targets cgas to inhibit type i interferon induction to promote other dna virus infection. |
| publisher |
Public Library of Science (PLoS) |
| publishDate |
2021 |
| url |
https://doaj.org/article/2d35ee003edf41508e1ef81301f9b5f7 |
| work_keys_str_mv |
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| _version_ |
1718375711225413632 |