State Key Laboratory of Natural Medicines, School of Life Science and Technology, China Pharmaceutical University, Nanjing, Jiangning District, China.
Center for Kidney Diseases, The 2nd Affiliated Hospital of Nanjing Medical University, Nanjing, China.
Autophagy. 2023 Feb;19(2):440-456. doi: 10.1080/15548627.2022.2076192. Epub 2022 May 30.
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 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 diseases: 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.
STING1（干扰素反应 cGAMP 相互作用因子 1 的刺激物）是 CGAS（环鸟苷酸-AMP 合酶）-STING1 信号转导的关键衔接蛋白，对先天免疫的 I 型 IFN 产生至关重要。然而，STING1 的过度或延长激活与自身炎症性和自身免疫性疾病有关。因此，防止 STING1 过度激活对于维持免疫平衡很重要。在这里，我们报道了 UXT（普遍表达的原核折叠酶样伴侣），一种小的伴侣样蛋白，通过 SQSTM1（自噬体相关蛋白 1）介导的自噬降解 STING1，是防止 STING1 介导的 I 型 IFN 信号过度激活所必需的。在 DNA 模拟物或环鸟苷酸-AMP（cGAMP）刺激下，UXT 特异性地与 STING1 相互作用，并通过选择性巨自噬/自噬促进 STING1 的降解。此外，UXT 通过促进 SQSTM1 和 STING1 的相互作用，促进 STING1 的自噬降解，从而提高 STING1 的降解效率。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-STING1 信号中的作用。有趣的是，在几个大的系统性红斑狼疮（SLE）队列的白细胞和外周血单核细胞（PBMCs）中，UXT 的表达持续受损，并表现出与 I 型 IFN 特征明显的负相关。重要的是，SLE 患者 PBMCs 中 UXT 的补充有效地抑制了 IFNs 和 ISGs 的产生。总之，我们的研究揭示了 UXT 在 STING1 自噬降解中的新的调节作用，以维持免疫平衡。UXT 可能是缓解自身免疫性疾病中异常 I 型 IFNs 的潜在治疗靶点：3-MA：3-甲基腺嘌呤；BMDMs：骨髓来源的巨噬细胞；cGAMP：环鸟苷酸-AMP；CGAS：环鸟苷酸-AMP 合酶；cKO：条件敲除；CXCL10：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；HTDNA：鲱鱼精 DNA；IFIT1：干扰素诱导的具有四肽重复的蛋白 1；IFNA4：干扰素 alpha 4；IFNB：干扰素 beta；IRF3：干扰素调节因子 3；ISD：干扰素刺激 DNA；ISGs：IFN 刺激基因；MAP1LC3B/LC3B：微管相关蛋白 1 轻链 3B；MEFs：小鼠胚胎成纤维细胞；RNA-seq：RNA 测序；PBMCs：外周血单核细胞；RSAD2：自由基 S-腺苷甲硫氨酸域包含 2；SLE：系统性红斑狼疮；SQSTM1：自噬体相关蛋白 1；STING1：干扰素反应 cGAMP 相互作用因子 1 的刺激物；TBK1：TANK 结合激酶 1；TMPD：2,6,10,14-四甲基十五烷；UXT：普遍表达的原核折叠酶样伴侣。
