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.