Spatiotemporal Regulation of STING Activity by Linear Ubiquitination Governs Antiviral Immunity
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.
Authors
- Yong Zhang (ORCID: https://orcid.org/0000-0001-6316-2734)
- Pupu Ge (ORCID: https://orcid.org/0000-0002-3499-6438)
- Cui Hua Liu (ORCID: https://orcid.org/0000-0002-8035-7792)
- Lingqiang Zhang (ORCID: https://orcid.org/0000-0002-9795-2141)
- Bing-Xi Li (ORCID: https://orcid.org/0000-0003-2512-4192)
- Lihua Qiang (ORCID: https://orcid.org/0000-0001-9285-6436)
- Qiyao Chai (ORCID: https://orcid.org/0000-0002-0454-7834)
- Zehui Lei
- Yesheng Fu (ORCID: https://orcid.org/0000-0002-3947-601X)
- Guoping Chen (ORCID: https://orcid.org/0000-0001-8157-4687)
- Zhuo Zhao (ORCID: https://orcid.org/0000-0002-9671-6614)
- Zhe Lü (ORCID: https://orcid.org/0009-0000-3999-1276)
- Meng Zhao (ORCID: https://orcid.org/0000-0001-7199-272X)
- Jing Wang
Institutions
- Chinese Academy of Sciences (CN)
- Institute of Microbiology (BY)
- Czech Academy of Sciences, Institute of Microbiology (CZ)
- Institute of Microbiology (CN)
- China Academy of Chinese Medical Sciences (CN)
- Beijing Proteome Research Center (CN)
- University of Chinese Academy of Sciences (CN)
- Tsinghua University (CN)
Publication Details
- Journal
- Advanced Science
- Published
- 2025-06-19
- DOI
- https://doi.org/10.1002/advs.202417660
- Citations
- 3
- Primary Topic
- interferon and immune responses
- Type
- article
- Field-Weighted Citation Impact
- 2.39
Funders
- National Natural Science Foundation of China
- National Key Research and Development Program of China