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Structural basis of human TREX1 DNA degradation and autoimmune disease

Author

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  • Wen Zhou

    (Southern University of Science and Technology)

  • Desmond Richmond-Buccola

    (Harvard Medical School
    Dana-Farber Cancer Institute)

  • Qiannan Wang

    (Southern University of Science and Technology)

  • Philip J. Kranzusch

    (Harvard Medical School
    Dana-Farber Cancer Institute
    Parker Institute for Cancer Immunotherapy at Dana-Farber Cancer Institute)

Abstract

TREX1 is a cytosolic DNA nuclease essential for regulation of cGAS-STING immune signaling. Existing structures of mouse TREX1 establish a mechanism of DNA degradation and provide a key model to explain autoimmune disease, but these structures incompletely explain human disease-associated mutations and have limited ability to guide development of small-molecule therapeutics. Here we determine crystal structures of human TREX1 in apo and DNA-bound conformations that provide high-resolution detail of all human-specific features. A 1.25 Å structure of human TREX1 establishes a complete model of solvation of the exonuclease active site and a 2.2 Å structure of the human TREX1–DNA complex enables identification of specific substitutions involved in DNA recognition. We map each TREX1 mutation associated with autoimmune disease and establish distinct categories of substitutions predicted to impact enzymatic function, protein stability, and interaction with cGAS-DNA liquid droplets. Our results explain how human-specific substitutions regulate TREX1 function and provide a foundation for structure-guided design of TREX1 therapeutics.

Suggested Citation

  • Wen Zhou & Desmond Richmond-Buccola & Qiannan Wang & Philip J. Kranzusch, 2022. "Structural basis of human TREX1 DNA degradation and autoimmune disease," Nature Communications, Nature, vol. 13(1), pages 1-9, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-32055-z
    DOI: 10.1038/s41467-022-32055-z
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    References listed on IDEAS

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    1. Andrea Ablasser & Marion Goldeck & Taner Cavlar & Tobias Deimling & Gregor Witte & Ingo Röhl & Karl-Peter Hopfner & Janos Ludwig & Veit Hornung, 2013. "cGAS produces a 2′-5′-linked cyclic dinucleotide second messenger that activates STING," Nature, Nature, vol. 498(7454), pages 380-384, June.
    2. Claire Vanpouille-Box & Amandine Alard & Molykutty J. Aryankalayil & Yasmeen Sarfraz & Julie M. Diamond & Robert J. Schneider & Giorgio Inghirami & C. Norman Coleman & Silvia C. Formenti & Sandra Dema, 2017. "DNA exonuclease Trex1 regulates radiotherapy-induced tumour immunogenicity," Nature Communications, Nature, vol. 8(1), pages 1-15, August.
    3. Camilo E. Quevedo & Abimael Cruz-Migoni & Nicolas Bery & Ami Miller & Tomoyuki Tanaka & Donna Petch & Carole J. R. Bataille & Lydia Y. W. Lee & Phillip S. Fallon & Hanna Tulmin & Matthias T. Ehebauer , 2018. "Small molecule inhibitors of RAS-effector protein interactions derived using an intracellular antibody fragment," Nature Communications, Nature, vol. 9(1), pages 1-12, December.
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    Cited by:

    1. Satoshi Kimura & Veerasak Srisuknimit & Kacie L. McCarty & Peter C. Dedon & Philip J. Kranzusch & Matthew K. Waldor, 2022. "Sequential action of a tRNA base editor in conversion of cytidine to pseudouridine," Nature Communications, Nature, vol. 13(1), pages 1-15, December.

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