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

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 Aletaha, Maojun Yang, Manuele Rebsamen (), Leonhard X. Heinz () and Giulio Superti-Furga ()
Additional contact information
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
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
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

Nature Communications, 2023, vol. 14, issue 1, 1-12

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-42070-3

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