Nitro-fatty acids are formed in response to virus infection and are potent inhibitors of STING palmitoylation and signaling.
Nitro-fatty acids are formed in response to virus infection and are potent inhibitors of STING palmitoylation and signaling.
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DOI：
10.1073/pnas.1806239115
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发表时间：
2018-08-14
影响因子：
11.1
通讯作者：
Holm CK
中科院分区：
文献类型：
--
作者：
Hansen AL;Buchan GJ;Rühl M;Mukai K;Salvatore SR;Ogawa E;Andersen SD;Iversen MB;Thielke AL;Gunderstofte C;Motwani M;Møller CT;Jakobsen AS;Fitzgerald KA;Roos J;Lin R;Maier TJ;Goldbach-Mansky R;Miner CA;Qian W;Miner JJ;Rigby RE;Rehwinkel J;Jakobsen MR;Arai H;Taguchi T;Schopfer FJ;Olagnier D;Holm CK
最近已证明几种慢性炎症状况取决于 IFN 基因信号蛋白刺激物 (STING) 的异常高活性。这些病症包括系统性红斑狼疮、Aicardi-Goutiéres 综合征和婴儿期发病的 STING 相关血管病。 STING 在这些疾病中的参与表明对识别 STING 信号传导抑制剂的需求尚未得到满足，这可能构成抗 STING 疗法的基础。通过这份报告，我们确定了不同的内源形成的脂质种类作为 STING 信号传导的有效抑制剂，并提出这些脂质可能具有治疗 STING 依赖性炎症疾病的药物潜力。 IFN 基因的衔接分子刺激物 (STING) 对于响应 DNA 病毒感染和细胞质中宿主 DNA 的存在而产生 I 型 IFN 至关重要。通过 STING 依赖性机制过度释放 I 型干扰素已成为多种干扰素病的核心驱动因素，包括系统性红斑狼疮 (SLE)、Aicardi-Goutières 综合征 (AGS) 和婴儿期发病的干扰素基因相关血管病刺激物 (SAVI)。 STING 与这些疾病的关系表明，开发抑制 STING 信号传导的药物的需求尚未得到满足。在这里，我们报道内源形成的硝基脂肪酸可以通过硝基烷基化共价修饰 STING。这些硝基烷基化抑制 STING 棕榈酰化、STING 信号传导，并随后抑制人类和小鼠细胞中 I 型 IFN 的释放。此外，硝基脂肪酸治疗足以抑制来自具有 STING 功能获得性突变的 SAVI 患者的成纤维细胞中 I 型 IFN 的产生。总之，我们已经确定硝基脂肪酸是 STING 信号传导的内源性抑制剂，并建议考虑将这些脂质用于治疗 STING 依赖性炎症疾病。
Several chronic inflammatory conditions have recently been shown to depend on abnormally high activity of the signaling protein stimulator of IFN genes (STING). These conditions include examples from systemic lupus erythematosus, Aicardi–Goutiéres syndrome, and STING-associated vasculopathy with onset in infancy. The involvement of STING in these diseases points to an unmet demand to identify inhibitors of STING signaling, which could form the basis of anti-STING therapeutics. With this report, we identify distinct endogenously formed lipid species as potent inhibitors of STING signaling—and propose that these lipids could have pharmaceutical potential for treatment of STING-dependent inflammatory diseases. The adaptor molecule stimulator of IFN genes (STING) is central to production of type I IFNs in response to infection with DNA viruses and to presence of host DNA in the cytosol. Excessive release of type I IFNs through STING-dependent mechanisms has emerged as a central driver of several interferonopathies, including systemic lupus erythematosus (SLE), Aicardi–Goutières syndrome (AGS), and stimulator of IFN genes-associated vasculopathy with onset in infancy (SAVI). The involvement of STING in these diseases points to an unmet need for the development of agents that inhibit STING signaling. Here, we report that endogenously formed nitro-fatty acids can covalently modify STING by nitro-alkylation. These nitro-alkylations inhibit STING palmitoylation, STING signaling, and subsequently, the release of type I IFN in both human and murine cells. Furthermore, treatment with nitro-fatty acids was sufficient to inhibit production of type I IFN in fibroblasts derived from SAVI patients with a gain-of-function mutation in STING. In conclusion, we have identified nitro-fatty acids as endogenously formed inhibitors of STING signaling and propose for these lipids to be considered in the treatment of STING-dependent inflammatory diseases.
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DOI：
10.1056/nejmoa1312625
发表时间：
2014-08-07
期刊：
The New England journal of medicine
影响因子：
--
作者：
Liu Y;Jesus AA;Marrero B;Yang D;Ramsey SE;Sanchez GAM;Tenbrock K;Wittkowski H;Jones OY;Kuehn HS;Lee CR;DiMattia MA;Cowen EW;Gonzalez B;Palmer I;DiGiovanna JJ;Biancotto A;Kim H;Tsai WL;Trier AM;Huang Y;Stone DL;Hill S;Kim HJ;St Hilaire C;Gurprasad S;Plass N;Chapelle D;Horkayne-Szakaly I;Foell D;Barysenka A;Candotti F;Holland SM;Hughes JD;Mehmet H;Issekutz AC;Raffeld M;McElwee J;Fontana JR;Minniti CP;Moir S;Kastner DL;Gadina M;Steven AC;Wingfield PT;Brooks SR;Rosenzweig SD;Fleisher TA;Deng Z;Boehm M;Paller AS;Goldbach-Mansky R
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Goldbach-Mansky R
DOI：
10.1126/science.1244040
发表时间：
2013-09-20
期刊：
Science (New York, N.Y.)
影响因子：
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影响因子：
16.8
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Huang, Yi-He;Liu, Xiang-Yu;Su, Xiao-Dong
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Su, Xiao-Dong
DOI：
10.1016/j.ymthe.2017.04.022
发表时间：
2017-08-02
期刊：
Molecular therapy : the journal of the American Society of Gene Therapy
影响因子：
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作者：
Olagnier D;Lababidi RR;Hadj SB;Sze A;Liu Y;Naidu SD;Ferrari M;Jiang Y;Chiang C;Beljanski V;Goulet ML;Knatko EV;Dinkova-Kostova AT;Hiscott J;Lin R
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Lin R
DOI：
10.1016/j.plefa.2010.02.021
发表时间：
2010-04-01
影响因子：
3
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通讯作者：
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