1区 · 综合性期刊
ArticleOA
作者: Xie, Min ; Rebsamen, Manuele ; Heinz, Leonhard X ; Boeszoermenyi, Andras ; Yang, Maojun ; Aletaha, Daniel ; Bernaleau, Léa ; Delacrétaz, Maeva ; Chen, Xudong ; Superti-Furga, Giulio ; Zhang, Haobo ; Kartnig, Felix ; Zhang, Sensen ; Koren, Anna ; Hopp, Ann-Katrin ; Kubicek, Stefan ; Dvorak, Vojtech
AbstractDysregulation 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.
