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Structural basis of human TREX1 DNA degradation and autoimmune disease

Wen Zhou1, Desmond Richmond-Buccola2,3, Qiannan Wang4

  • 1Department of Immunology and Microbiology, School of Life Sciences, Southern University of Science and Technology, Shenzhen, Guangdong, 518055, China. zhouw@sustech.edu.cn.

Nature Communications
|July 25, 2022
PubMed

Insights

Human TREX1 structures reveal how mutations cause autoimmune disease and guide therapeutic development. These findings explain TREX1 function and its role in immune signaling, paving the way for new treatments.

Area of Science:

  • Biochemistry
  • Structural Biology
  • Immunology

Background:

  • TREX1 (three prime repair exonuclease 1) is a crucial enzyme regulating the cGAS-STING innate immune pathway by degrading cytosolic DNA.
  • Dysregulation of TREX1 is linked to autoimmune diseases, but existing structural data from mouse models incompletely explain human disease mechanisms and therapeutic targeting.
  • Understanding human TREX1 structure is vital for elucidating disease pathogenesis and developing targeted therapies.

Purpose of the Study:

  • To determine high-resolution crystal structures of human TREX1 in both apo and DNA-bound states.
  • To characterize human-specific structural features and their implications for enzymatic function and disease.
  • To provide a structural basis for understanding human TREX1 mutations associated with autoimmune diseases and for designing therapeutics.

Main Methods:

  • X-ray crystallography was used to obtain structures of human TREX1.
  • Apo and DNA-bound structures were determined at 1.25 Å and 2.2 Å resolution, respectively.
  • Structure-based analysis was performed to map disease-associated mutations and their functional impact.

Main Results:

  • High-resolution structures of human TREX1 in apo and DNA-bound conformations were determined, detailing human-specific features.
  • The structures reveal complete solvation of the exonuclease active site and specific DNA recognition mechanisms.
  • Disease-associated human TREX1 mutations were categorized based on their predicted impact on enzymatic function, protein stability, and interactions with cGAS-DNA condensates.

Conclusions:

  • The determined human TREX1 structures provide unprecedented detail on enzyme function and regulation.
  • These findings elucidate how human-specific substitutions contribute to autoimmune disease pathogenesis.
  • The study offers a structural foundation for the rational design of small-molecule therapeutics targeting TREX1 for autoimmune conditions.

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