UXT attenuates the CGAS-STING1 signaling by targeting STING1 for autophagic degradation

• DOI: 10.1080/15548627.2022.2076192
• Publication Date: 2022-05-11T09:24:42Z
• Authors: Mingyu Pan; Yue Yin; Tongyu Hu; Xinxia Wang; Tian Jia; Jing Sun; Quanyi Wang; Wei Meng; Juanjuan Zhu; Chunsun Dai; Haiyang Hu; Chen Wang
• Keywords: HEK 293 cells

STING1 (stimulator of interferon response cGAMP interactor 1), the pivotal adaptor protein CGAS (cyclic GMP-AMP synthase)-STING1 signaling, is critical for type I IFN production innate immunity. However, excessive or prolonged activation associated with autoinflammatory and autoimmune diseases. Thus, preventing from over-activation important to maintain immune homeostasis. Here, we reported that UXT (ubiquitously expressed prefoldin like chaperone), a small chaperone-like protein, was essential prevent STING1-mediated signaling through autophagic degradation via SQSTM1 (sequestosome 1). Upon DNA mimics cyclic (cGAMP) stimulation, specifically interacted promoted selective macroautophagy/autophagy. Moreover, required more efficient by facilitating interaction STING1. The in vivo role attenuating CGAS-STING1 further confirmed mouse model DNA-virus infection TMPD (2,6,10,14-tetramethylpentadecane)-induced murine lupus model. Intriguingly, expression consistently impaired exhibited remarkable inverse correlation signature leukocytes PBMCs (peripheral blood mononuclear cells) several large SLE (systemic erythematosus) cohorts. Importantly, replenishment effectively suppressed IFNs ISGs patients. Taken together, our study reveals novel regulatory might be potential therapeutic target alleviating aberrant diseasesAbbreviations: 3-MA: 3-methyladenine; BMDMs: bone marrow-derived macrophages; cGAMP: GMP-AMP; CGAS: gmp-amp synthase; cKO: conditional knockout; CXCL10: C-X-C motif chemokine ligand 10; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; HSV-1: herpes simplex virus 1; HTDNA: herring testes DNA; IFIT1: induced tetratricopeptide repeats IFNA4: alpha 4; IFNB: beta; IRF3: factor 3; ISD: stimulatory ISGs: IFN-stimulated genes; MAP1LC3B/LC3B: microtubule 1 light chain 3 MEFs: embryonic fibroblasts; RNA-seq: RNA sequencing; PBMCs: peripheral cells; RSAD2: radical S-adenosyl methionine domain containing 2; SLE: systemic erythematosus; SQSTM1: sequestosome STING1: stimulator TBK1: TANK binding kinase TMPD: 2,6,10,14-tetramethylpentadecane; UXT: ubiquitously chaperone.