A Conformation-locking Inhibitor of SLC15A4 with TASL Proteostatic Anti-inflammatory Activity

Overview

Journal Nat Commun

Specialty Biology

Date 2023 Oct 20

PMID 37863876

Authors

Andras Boeszoermenyi

Lea Bernaleau

Xudong Chen

Felix Kartnig

Min Xie

Haobo Zhang

Sensen Zhang

Maeva Delacretaz

Anna Koren

Ann-Katrin Hopp

Vojtech Dvorak

Stefan Kubicek

Daniel Aletaha

Maojun Yang

Manuele Rebsamen

Leonhard X Heinz

Giulio Superti-Furga

Affiliations

Soon will be listed here.

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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