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

  • Nat Commun. 2023 Oct 20;14(1):6626. doi: 10.1038/s41467-023-42070-3.
Andras Boeszoermenyi  1 ,  Léa Bernaleau  #  2 ,  Xudong Chen  #  3 ,  Felix Kartnig  1  4 ,  Min Xie  3 ,  Haobo Zhang  2 ,  Sensen Zhang  3 ,  Maeva Delacrétaz  2 ,  Anna Koren  1 ,  Ann-Katrin Hopp  1 ,  Vojtech Dvorak  1 ,  Stefan Kubicek  1 ,  Daniel Aletaha  4 ,  Maojun Yang  3  5 ,  Manuele Rebsamen  6 ,  Leonhard X Heinz  7 ,  Giulio Superti-Furga  8  9
Affiliations
  • 1. CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
  • 2. Department of Immunobiology, University of Lausanne, Epalinges, Switzerland.
  • 3. Ministry of Education Key Laboratory of Protein Science, Tsinghua-Peking Center for Life Sciences, Beijing Advanced Innovation Center for Structural Biology, School of Life Sciences, Tsinghua University, Beijing, China.
  • 4. Division of Rheumatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria.
  • 5. Cryo-EM Facility Center, Southern University of Science & Technology, Shenzhen, Guangdong, China.
  • 6. Department of Immunobiology, University of Lausanne, Epalinges, Switzerland. [email protected].
  • 7. Division of Rheumatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria. [email protected].
  • 8. CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria. [email protected].
  • 9. Center for Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria. [email protected].
  • # Contributed equally.
PMID: 37863876 DOI: 10.1038/s41467-023-42070-3
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.

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