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A conformation-locking inhibitor of SLC15A4 with TASL proteostatic anti-inflammatory activity

Author

Listed:
  • Andras Boeszoermenyi

    (CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences)

  • Léa Bernaleau

    (University of Lausanne)

  • Xudong Chen

    (Tsinghua University)

  • Felix Kartnig

    (CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences
    Medical University of Vienna)

  • Min Xie

    (Tsinghua University)

  • Haobo Zhang

    (University of Lausanne)

  • Sensen Zhang

    (Tsinghua University)

  • Maeva Delacrétaz

    (University of Lausanne)

  • Anna Koren

    (CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences)

  • Ann-Katrin Hopp

    (CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences)

  • Vojtech Dvorak

    (CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences)

  • Stefan Kubicek

    (CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences)

  • Daniel Aletaha

    (Medical University of Vienna)

  • Maojun Yang

    (Tsinghua University
    Southern University of Science & Technology)

  • Manuele Rebsamen

    (University of Lausanne)

  • Leonhard X. Heinz

    (Medical University of Vienna)

  • Giulio Superti-Furga

    (CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences
    Medical University of Vienna)

Abstract

Dysregulation of pathogen-recognition pathways of the innate immune system is associated with multiple autoimmune disorders. Due to the intricacies of the molecular network involved, the identification of pathway- and disease-specific therapeutics has been challenging. Using a phenotypic assay monitoring the degradation of the immune adapter TASL, we identify feeblin, a chemical entity which inhibits the nucleic acid-sensing TLR7/8 pathway activating IRF5 by disrupting the SLC15A4-TASL adapter module. A high-resolution cryo-EM structure of feeblin with SLC15A4 reveals that the inhibitor binds a lysosomal outward-open conformation incompatible with TASL binding on the cytoplasmic side, leading to degradation of TASL. This mechanism of action exploits a conformational switch and converts a target-binding event into proteostatic regulation of the effector protein TASL, interrupting the TLR7/8-IRF5 signaling pathway and preventing downstream proinflammatory responses. Considering that all components involved have been genetically associated with systemic lupus erythematosus and that feeblin blocks responses in disease-relevant human immune cells from patients, the study represents a proof-of-concept for the development of therapeutics against this disease.

Suggested Citation

  • Andras Boeszoermenyi & Léa Bernaleau & Xudong Chen & Felix Kartnig & Min Xie & Haobo Zhang & Sensen Zhang & Maeva Delacrétaz & Anna Koren & Ann-Katrin Hopp & Vojtech Dvorak & Stefan Kubicek & Daniel A, 2023. "A conformation-locking inhibitor of SLC15A4 with TASL proteostatic anti-inflammatory activity," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-42070-3
    DOI: 10.1038/s41467-023-42070-3
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