Spatiotemporal Regulation of STING Activity by Linear Ubiquitination Governs Antiviral Immunity
Abstract The cyclic GMP‐AMP synthase (cGAS)‐stimulator of interferon gene protein (STING) signaling plays a critical role in innate immunity and must be tightly regulated to maintain immune homeostasis, but the mechanism underlying the spatiotemporal regulation of this pathway remains largely elusiv...
Saved in:
| Main Authors: | , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Wiley
2025-07-01
|
| Series: | Advanced Science |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/advs.202417660 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1850059535964700672 |
|---|---|
| author | Yong Zhang Yesheng Fu Lihua Qiang Mengyuan Zhao Zhe Lu Zhuo Zhao Guoping Chen Zehui Lei Qiyao Chai Pupu Ge Bingxi Li Jing Wang Cui Hua Liu Lingqiang Zhang |
| author_facet | Yong Zhang Yesheng Fu Lihua Qiang Mengyuan Zhao Zhe Lu Zhuo Zhao Guoping Chen Zehui Lei Qiyao Chai Pupu Ge Bingxi Li Jing Wang Cui Hua Liu Lingqiang Zhang |
| author_sort | Yong Zhang |
| collection | DOAJ |
| description | Abstract The cyclic GMP‐AMP synthase (cGAS)‐stimulator of interferon gene protein (STING) signaling plays a critical role in innate immunity and must be tightly regulated to maintain immune homeostasis, but the mechanism underlying the spatiotemporal regulation of this pathway remains largely elusive. Here, it is shown that during DNA viral infection, the linear ubiquitin chain assembly complex (LUBAC) and ovarian tumor deubiquitinase with linear linkage specificity (OTULIN) reversibly catalyze the linear ubiquitination of STING. At the early stage of the infection, LUBAC promotes STING linear ubiquitination to drive its trafficking from the endoplasmic reticulum (ER) to the Golgi apparatus through binding to the Sec24b subunit of the coat protein complex II (COPII) complex. Later on, OTULIN is recruited to TANK1 binding kinase 1 (TBK1)‐phosphorylated STING and removes its linear ubiquitin chains, thus preventing excessive antiviral immune responses. Together, the study uncovers a linear ubiquitination‐governed spatiotemporal regulatory mechanism that fine‐tunes STING‐driven antiviral immunity. |
| format | Article |
| id | doaj-art-a36ae1386e8a495c8cbe0bf324b061d5 |
| institution | DOAJ |
| issn | 2198-3844 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Science |
| spelling | doaj-art-a36ae1386e8a495c8cbe0bf324b061d52025-08-20T02:50:52ZengWileyAdvanced Science2198-38442025-07-011228n/an/a10.1002/advs.202417660Spatiotemporal Regulation of STING Activity by Linear Ubiquitination Governs Antiviral ImmunityYong Zhang0Yesheng Fu1Lihua Qiang2Mengyuan Zhao3Zhe Lu4Zhuo Zhao5Guoping Chen6Zehui Lei7Qiyao Chai8Pupu Ge9Bingxi Li10Jing Wang11Cui Hua Liu12Lingqiang Zhang13School of Medicine Tsinghua University Beijing 100084 ChinaState Key Laboratory of Medical Proteomics Beijing Proteome Research Center National Center for Protein Sciences (Beijing) Beijing Institute of Lifeomics Beijing 102206 ChinaLaboratory of Pathogen Microbiology and Immunology Institute of Microbiology Chinese Academy of Sciences Beijing 100101 ChinaLaboratory of Pathogen Microbiology and Immunology Institute of Microbiology Chinese Academy of Sciences Beijing 100101 ChinaLaboratory of Pathogen Microbiology and Immunology Institute of Microbiology Chinese Academy of Sciences Beijing 100101 ChinaLaboratory of Pathogen Microbiology and Immunology Institute of Microbiology Chinese Academy of Sciences Beijing 100101 ChinaLaboratory of Pathogen Microbiology and Immunology Institute of Microbiology Chinese Academy of Sciences Beijing 100101 ChinaLaboratory of Pathogen Microbiology and Immunology Institute of Microbiology Chinese Academy of Sciences Beijing 100101 ChinaLaboratory of Pathogen Microbiology and Immunology Institute of Microbiology Chinese Academy of Sciences Beijing 100101 ChinaLaboratory of Pathogen Microbiology and Immunology Institute of Microbiology Chinese Academy of Sciences Beijing 100101 ChinaLaboratory of Pathogen Microbiology and Immunology Institute of Microbiology Chinese Academy of Sciences Beijing 100101 ChinaLaboratory of Pathogen Microbiology and Immunology Institute of Microbiology Chinese Academy of Sciences Beijing 100101 ChinaLaboratory of Pathogen Microbiology and Immunology Institute of Microbiology Chinese Academy of Sciences Beijing 100101 ChinaState Key Laboratory of Medical Proteomics Beijing Proteome Research Center National Center for Protein Sciences (Beijing) Beijing Institute of Lifeomics Beijing 102206 ChinaAbstract The cyclic GMP‐AMP synthase (cGAS)‐stimulator of interferon gene protein (STING) signaling plays a critical role in innate immunity and must be tightly regulated to maintain immune homeostasis, but the mechanism underlying the spatiotemporal regulation of this pathway remains largely elusive. Here, it is shown that during DNA viral infection, the linear ubiquitin chain assembly complex (LUBAC) and ovarian tumor deubiquitinase with linear linkage specificity (OTULIN) reversibly catalyze the linear ubiquitination of STING. At the early stage of the infection, LUBAC promotes STING linear ubiquitination to drive its trafficking from the endoplasmic reticulum (ER) to the Golgi apparatus through binding to the Sec24b subunit of the coat protein complex II (COPII) complex. Later on, OTULIN is recruited to TANK1 binding kinase 1 (TBK1)‐phosphorylated STING and removes its linear ubiquitin chains, thus preventing excessive antiviral immune responses. Together, the study uncovers a linear ubiquitination‐governed spatiotemporal regulatory mechanism that fine‐tunes STING‐driven antiviral immunity.https://doi.org/10.1002/advs.202417660antiviral immunityHOIPlinear ubiquitinationOTULINSTING |
| spellingShingle | Yong Zhang Yesheng Fu Lihua Qiang Mengyuan Zhao Zhe Lu Zhuo Zhao Guoping Chen Zehui Lei Qiyao Chai Pupu Ge Bingxi Li Jing Wang Cui Hua Liu Lingqiang Zhang Spatiotemporal Regulation of STING Activity by Linear Ubiquitination Governs Antiviral Immunity Advanced Science antiviral immunity HOIP linear ubiquitination OTULIN STING |
| title | Spatiotemporal Regulation of STING Activity by Linear Ubiquitination Governs Antiviral Immunity |
| title_full | Spatiotemporal Regulation of STING Activity by Linear Ubiquitination Governs Antiviral Immunity |
| title_fullStr | Spatiotemporal Regulation of STING Activity by Linear Ubiquitination Governs Antiviral Immunity |
| title_full_unstemmed | Spatiotemporal Regulation of STING Activity by Linear Ubiquitination Governs Antiviral Immunity |
| title_short | Spatiotemporal Regulation of STING Activity by Linear Ubiquitination Governs Antiviral Immunity |
| title_sort | spatiotemporal regulation of sting activity by linear ubiquitination governs antiviral immunity |
| topic | antiviral immunity HOIP linear ubiquitination OTULIN STING |
| url | https://doi.org/10.1002/advs.202417660 |
| work_keys_str_mv | AT yongzhang spatiotemporalregulationofstingactivitybylinearubiquitinationgovernsantiviralimmunity AT yeshengfu spatiotemporalregulationofstingactivitybylinearubiquitinationgovernsantiviralimmunity AT lihuaqiang spatiotemporalregulationofstingactivitybylinearubiquitinationgovernsantiviralimmunity AT mengyuanzhao spatiotemporalregulationofstingactivitybylinearubiquitinationgovernsantiviralimmunity AT zhelu spatiotemporalregulationofstingactivitybylinearubiquitinationgovernsantiviralimmunity AT zhuozhao spatiotemporalregulationofstingactivitybylinearubiquitinationgovernsantiviralimmunity AT guopingchen spatiotemporalregulationofstingactivitybylinearubiquitinationgovernsantiviralimmunity AT zehuilei spatiotemporalregulationofstingactivitybylinearubiquitinationgovernsantiviralimmunity AT qiyaochai spatiotemporalregulationofstingactivitybylinearubiquitinationgovernsantiviralimmunity AT pupuge spatiotemporalregulationofstingactivitybylinearubiquitinationgovernsantiviralimmunity AT bingxili spatiotemporalregulationofstingactivitybylinearubiquitinationgovernsantiviralimmunity AT jingwang spatiotemporalregulationofstingactivitybylinearubiquitinationgovernsantiviralimmunity AT cuihualiu spatiotemporalregulationofstingactivitybylinearubiquitinationgovernsantiviralimmunity AT lingqiangzhang spatiotemporalregulationofstingactivitybylinearubiquitinationgovernsantiviralimmunity |