MOLECULAR CELL
·
2023
·
IF 16
Sheng Liu,Bo Yang,Yingxiang Hou,Kaige Cui,Xiaozhu Yang,Xiaoxiong Li,Lianwan Chen,Shichao Liu,Zhichao Zhang,Yuanyuan Jia,Yufeng Xie,Ying Xue,Xiaomei Li,Bingxue Yan,Changxin Wu,Wen Deng,Jianxun Qi,Defen Lu,George F. Gao,Peiyi Wang,Guijun Shang
Summary 2′,3′-cGAMP, produced by the DNA sensor cGAS, activates stimulator of interferon genes (STING) and triggers immune response during infection. Tremendous effort has been placed on unraveling the mechanism of STING activation. However, little is known about STING inhibition. Here, we found that apo-STING exhibits a bilayer with head-to-head as well as side-by-side packing, mediated by its ligand-binding domain (LBD). This type of assembly holds two endoplasmic reticulum (ER) membranes together not only to prevent STING ER exit but also to eliminate the recruitment of TBK1, representing the autoinhibited state of STING. Additionally, we obtained the filament structure of the STING/2′,3′-cGAMP complex, which adopts a bent monolayer assembly mediated by LBD and transmembrane domain (TMD). The active, curved STING polymer could deform ER membrane to support its ER exit and anterograde transportation. Our data together provide a panoramic vision regarding STING autoinhibition and activation, which adds substantially to current understanding of the cGAS-STING pathway.
研究领域:
免疫学
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细胞生物学
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分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Cell Reports
·
2026
·Vol. 45
·期 4
·
IF 7.7
Yun Lv,Sheng Liu,Qihai Wang,Jing Zhu,Yingxiang Hou,Haiyan Xu,Deyan Zhu,Yu Liu,Jing Wu,Changxin Wu,Guijun Shang,Hongxiang Lou,Defen Lu,Huiqing Yuan,Deyu Zhu
The cyclic-oligonucleotide-based antiphage signaling system (CBASS) protects bacteria from phage infection. In Vibrio cholerae , phage infection activates CD-NTase DncV to produce 3′3′-cGAMP, which triggers phospholipase CapV to degrade phosphatidylethanolamine and phosphatidylglycerol, the major phospholipids in the inner-membranes, thereby inducing cell death. However, how 3′3′-cGAMP activates CapV was unclear. Here we present crystal structures of inactive Acinetobacter baumannii CapV in apo and 3′3′-cGAMP-bound forms, along with cryo-EM structures of activated CapV-3′3′-cGAMP complex, with or without substrate dioleoylphosphatidyl-ethanolamine (DOPE). Apo-CapV forms symmetric dimers in a “closed” state. 3′3′-cGAMP binding drives lateral polymerization of dimers into filament assembly, inducing an “open” state that exposes the active site and substrate-binding cleft. DOPE binding further shifts CapV to an “ajar” state, where a Y-shaped cleft positions DOPE for hydrolysis via a conserved Ser/Asp catalytic dyad. This 3′3′-cGAMP-induced filamentation mirrors activation mechanisms of TIR-STING, TIR-SAVED, and mammalian STING, revealing a conserved signaling pattern across immune systems.
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DOI
PubMed
高影响因子
JOURNAL OF CONTROLLED RELEASE
·
2022
·
IF 11.467
Hong Liu,Zhitao Hu,Haolin Chen,Yanzi Yan,Zhicheng Le,Cong Wei,Wenqiang Cao,Tianfeng Chen,Yongming Chen,Lixin Liu
Vaccination with subunit nanovaccines is a promising strategy to combat virus infection and tumor development. However, immunogenicity of present nanovaccines is still unsatisfied for clinical translation. Here, we developed a nanovaccine loading a STING agonist, 2′3′-cGAMP and, a model subunit antigen, OVA , by using a well-defined self-degradable poly(β-amino ester)s to treat B16F10-OVA melanoma tumors. The polymer underwent slow hydrolysis at pH 5.5 but self-degraded induced by the amino groups along the polyester chain at pH > 6.5. It is shown that the self-degradation products facilitated the release of 2′3′-cGAMP and OVA from early endolysome to the cytosol, where the two components strongly activated CD8 + T lymphocytes (CTLs) and significantly enhanced Ifn1, TNF , Cxcl9, and Cxcl10 expression. In turn, the tumor microenvironment was remolded from cold to hot. Moreover, the nanovaccine could be quickly drained to sentinel lymph nodes after intratumoral injection. The nanovaccine with strong immunogenicity also could reduce the side effects of systemic inflammatory reaction caused by molecular 2′3′-cGAMP. The tumor progression of animals was inhibited, and their survival rates increased significantly. Thus, the multifunctional biodegradable material provided a new delivery system for a cancer vaccine to translate to clinics.
研究领域:
癌症研究
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免疫学
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生物医学工程
·
分子生物学
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产品关联
DOI
PubMed
高影响因子
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