UXT attenuates the CGAS-STING1 signaling by targeting STING1 for autophagic degradation
UXT attenuates the CGAS-STING1 signaling by targeting STING1 for autophagic degradation
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UXT 通过靶向 STING1 进行自噬降解来减弱 CGAS-STING1 信号传导
DOI：
10.1080/15548627.2022.2076192
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发表时间：
2022-05
期刊：
影响因子：
13.3
通讯作者：
Chen Wang
中科院分区：
文献类型：
--
作者：
Mingyu Pan;Yue Yin;Tongyu Hu;Xinxia Wang;Tian Jia;Jing Sun;Quanyi Wang;Wei Meng;Juanjuan Zhu;Chunsun Dai;Haiyang Hu;Chen Wang
STING 1（stimulator of interferon response cGAMP interactor 1）是CGAS（cyclicGMP-AMP synthase）-STING 1信号通路中的关键衔接蛋白，在天然免疫中I型干扰素（IFN）的产生中起着关键作用。然而，STING 1的过度或长期激活与自身炎症和自身免疫性疾病有关。因此，防止STING 1过度激活对维持免疫稳态很重要。在这里，我们报道了UXT（普遍表达的前折叠蛋白样伴侣蛋白），一种小的伴侣蛋白样蛋白，是必不可少的，以防止STING 1介导的I型IFN信号通过自噬降解STING 1通过SQSTM 1（隔离体1）的过度激活。在DNA模拟物或环GMP-AMP（cGAMP）刺激下，UXT特异性地与STING 1相互作用，并通过选择性大自噬/自噬促进STING 1降解。此外，UXT通过促进SQSTM 1和STING 1的相互作用来更有效地自噬降解STING 1。在DNA病毒感染的小鼠模型和TMPD（2，6，10，14-四甲基十五烷）诱导的小鼠狼疮模型中进一步证实了UXT在减弱CGAS-STING 1信号传导中的体内作用。有趣的是，UXT的表达始终受损，并表现出显着的负相关性与I型IFN签名在白细胞和PBMC（外周血单核细胞）的几个大型SLE（系统性红斑狼疮）队列。重要的是，补充UXT有效地抑制了SLE患者PBMC中IFN和ISG的产生。总之，我们的研究揭示了UXT在STING 1自噬降解中的新调节作用，以维持免疫稳态。UXT可能是缓解自身免疫性疾病中异常I型IFN的潜在治疗靶点。缩略语：3-MA：3-甲基腺嘌呤; BMDM：骨髓源性巨噬细胞; cGAMP：环GMP-AMP; CGAS：环GMP-AMP合酶; cKO：条件性敲除; CXCL 10：C-X-C基序趋化因子配体10; GAPDH：甘油醛-3-磷酸脱氢酶; HSV-1：单纯疱疹病毒1型; HTDNA：鲱鱼睾丸DNA; IFIT 1：干扰素诱导蛋白，具有三肽重复序列1; IFNA 4：干扰素α 4; IFNB：干扰素β; IRF 3：干扰素调节因子3; ISD：干扰素刺激DNA; ISG：干扰素刺激基因; MAP 1 LC 3B/LC 3B：微管相关蛋白1轻链3 β; MEF：小鼠胚胎成纤维细胞; RNA-seq：RNA测序; PBMC：外周血单核细胞; RSAD 2：含自由基S-腺苷甲硫氨酸结构域2; SLE：系统性红斑狼疮; SQSTM 1：隔离体1; STING 1：干扰素应答刺激因子cGAMP相互作用因子1; TBK 1：TANK结合激酶1; TMPD：2，6，10，14-四甲基十五烷; UXT：普遍表达的前折叠蛋白样伴侣。
ABSTRACT STING1 (stimulator of interferon response cGAMP interactor 1), the pivotal adaptor protein of CGAS (cyclic GMP-AMP synthase)-STING1 signaling, is critical for type I IFN production of innate immunity. However, excessive or prolonged activation of STING1 is associated with autoinflammatory and autoimmune diseases. Thus, preventing STING1 from over-activation is important to maintain immune homeostasis. Here, we reported that UXT (ubiquitously expressed prefoldin like chaperone), a small chaperone-like protein, was essential to prevent the excessive activation of STING1-mediated type I IFN signaling through autophagic degradation of STING1 via SQSTM1 (sequestosome 1). Upon DNA mimics or cyclic GMP-AMP (cGAMP) stimulation, UXT specifically interacted with STING1 and promoted STING1 degradation through selective macroautophagy/autophagy. Moreover, UXT was required for more efficient autophagic degradation of STING1 by facilitating the interaction of SQSTM1 and STING1. The in vivo role of UXT in attenuating the CGAS-STING1 signaling was further confirmed in the mouse model of DNA-virus infection and the TMPD (2,6,10,14-tetramethylpentadecane)-induced murine lupus model. Intriguingly, the expression of UXT was consistently impaired and exhibited a remarkable inverse correlation with type I IFN signature in the leukocytes and PBMCs (peripheral blood mononuclear cells) of several large SLE (systemic lupus erythematosus) cohorts. Importantly, the replenishment of UXT effectively suppressed the production of IFNs and ISGs in the PBMCs of SLE patients. Taken together, our study reveals a novel regulatory role of UXT in autophagic degradation of STING1 to maintain immune homeostasis. UXT might be a potential therapeutic target for alleviating aberrant type I IFNs in autoimmune diseasesAbbreviations: 3-MA: 3-methyladenine; BMDMs: bone marrow-derived macrophages; cGAMP: cyclic GMP-AMP; CGAS: cyclic gmp-amp synthase; cKO: conditional knockout; CXCL10: C-X-C motif chemokine ligand 10; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; HSV-1: herpes simplex virus type 1; HTDNA: herring testes DNA; IFIT1: interferon induced protein with tetratricopeptide repeats 1; IFNA4: interferon alpha 4; IFNB: interferon beta; IRF3: interferon regulatory factor 3; ISD: interferon stimulatory DNA; ISGs: IFN-stimulated genes; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; MEFs: mouse embryonic fibroblasts; RNA-seq: RNA sequencing; PBMCs: peripheral blood mononuclear cells; RSAD2: radical S-adenosyl methionine domain containing 2; SLE: systemic lupus erythematosus; SQSTM1: sequestosome 1; STING1: stimulator of interferon response cGAMP interactor 1; TBK1: TANK binding kinase 1; TMPD: 2,6,10,14-tetramethylpentadecane; UXT: ubiquitously expressed prefoldin like chaperone.
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DOI：
10.1126/science.aac7442
发表时间：
2015-10-23
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Hung T;Pratt GA;Sundararaman B;Townsend MJ;Chaivorapol C;Bhangale T;Graham RR;Ortmann W;Criswell LA;Yeo GW;Behrens TW
通讯作者：
Behrens TW
UXT 缺陷小鼠通过异常自噬激活表现出视网膜色素变性样特征
影响因子：
13.3
作者：
Pan M;Yin Y;Wang X;Wang Q;Zhang L;Hu H;Wang C
通讯作者：
Wang C
固有免疫力形成干细胞的病毒抗性。
影响因子：
64.5
作者：
Wu X;Dao Thi VL;Huang Y;Billerbeck E;Saha D;Hoffmann HH;Wang Y;Silva LAV;Sarbanes S;Sun T;Andrus L;Yu Y;Quirk C;Li M;MacDonald MR;Schneider WM;An X;Rosenberg BR;Rice CM
通讯作者：
Rice CM
影响因子：
13.3
作者：
Chiche, Laurent;Jourde-Chiche, Noemie;Whalen, Elizabeth;Presnell, Scott;Gersuk, Vivian;Dang, Kristen;Anguiano, Esperanza;Quinn, Charlie;Burtey, Stephane;Berland, Yvon;Kaplanski, Gilles;Harle, Jean-Robert;Pascual, Virginia;Chaussabel, Damien
通讯作者：
Chaussabel, Damien
影响因子：
32.4
作者：
Paludan SR;Bowie AG
通讯作者：
Bowie AG