endolysosomal transporter / PROTEIN TRANSPORT-INHIBITOR COMPLEX
Function / homology
Function and homology information
L-histidine transmembrane transporter activity / histidine transport / mast cell homeostasis / L-histidine transmembrane export from vacuole / peptidoglycan transmembrane transporter activity / Proton/oligopeptide cotransporters / regulation of isotype switching to IgG isotypes / positive regulation of toll-like receptor 8 signaling pathway / peptidoglycan transport / positive regulation of nucleotide-binding oligomerization domain containing 1 signaling pathway ...L-histidine transmembrane transporter activity / histidine transport / mast cell homeostasis / L-histidine transmembrane export from vacuole / peptidoglycan transmembrane transporter activity / Proton/oligopeptide cotransporters / regulation of isotype switching to IgG isotypes / positive regulation of toll-like receptor 8 signaling pathway / peptidoglycan transport / positive regulation of nucleotide-binding oligomerization domain containing 1 signaling pathway / positive regulation of toll-like receptor 7 signaling pathway / dipeptide import across plasma membrane / peptide:proton symporter activity / dipeptide transmembrane transporter activity / positive regulation of toll-like receptor 9 signaling pathway / positive regulation of nucleotide-binding oligomerization domain containing 2 signaling pathway / regulation of nucleotide-binding domain, leucine rich repeat containing receptor signaling pathway / endolysosome membrane / positive regulation of innate immune response / specific granule membrane / monoatomic ion transport / protein transport / early endosome membrane / lysosomal membrane / innate immune response / Neutrophil degranulation / membrane / plasma membrane Similarity search - Function
PTR2 family proton/oligopeptide symporters signature 2. / PTR2 family proton/oligopeptide symporter, conserved site / Proton-dependent oligopeptide transporter family / POT family / MFS transporter superfamily Similarity search - Domain/homology
National Natural Science Foundation of China (NSFC)
21532004, 31570733
China
Citation
Journal: Nat Commun / Year: 2023 Title: A conformation-locking inhibitor of SLC15A4 with TASL proteostatic anti-inflammatory activity. Authors: Andras Boeszoermenyi / Léa Bernaleau / Xudong Chen / Felix Kartnig / Min Xie / Haobo Zhang / Sensen Zhang / Maeva Delacrétaz / Anna Koren / Ann-Katrin Hopp / Vojtech Dvorak / Stefan ...Authors: 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 / Giulio Superti-Furga / 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 ...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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