Autoinflammatory syndromes of STING and TREX1 dysfunction

Area of Science:

• Genetics
• Immunology
• Molecular Biology

Background:

• Cytosolic DNA sensing via cyclic GMP-AMP synthase (cGAS) and stimulator of interferon genes (STING) activates innate immunity.
• The DNA-degrading enzyme three-prime repair exonuclease 1 (TREX1) negatively regulates this pathway; TREX1 loss-of-function causes cytosolic DNA accumulation and STING-mediated autoinflammation.
• STING gain-of-function mutations lead to STING-associated vasculopathy, a severe multi-organ disease.

Purpose of the Study:

• To elucidate the complex relationships between cytosolic DNA sensing, genome instability, and autoimmune disease phenotypes.
• To investigate the role of the TREX1-cGAS-STING pathway in both autoimmune diseases and DNA damage syndromes.
• To identify potential therapeutic targets for rare genetic disorders.

Main Methods:

• Review of genetic research on rare diseases.
• Analysis of molecular mechanisms involving TREX1, cGAS, and STING.
• Clinical correlation of monogenic autoimmune diseases and DNA damage syndromes.

Main Results:

• TREX1 deficiency causes cytosolic DNA buildup, leading to STING-driven autoinflammation and autoimmune phenotypes.
• Aberrant nuclear activity of mislocalized TREX1 causes genomic DNA damage, resulting in multi-organ degeneration and autoimmunity (e.g., retinal vasculopathy with cerebral leukoencephalopathy).
• The TREX1-cGAS-STING pathway is crucial for both innate immunity regulation and genome stability maintenance.

Conclusions:

• Monogenic autoimmune diseases and DNA damage syndromes exhibit clinical overlap, highlighting shared molecular pathways.
• Dysregulation of the TREX1-cGAS-STING pathway is central to several rare genetic disorders.
• Understanding these pathways opens avenues for developing novel small molecule therapeutics for these debilitating conditions.