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Structural basis for recruitment of TASL by SLC15A4 in human endolysosomal TLR signaling

Authors :
Xudong Chen
Min Xie
Sensen Zhang
Marta Monguió-Tortajada
Jian Yin
Chang Liu
Youqi Zhang
Maeva Delacrétaz
Mingyue Song
Yixue Wang
Lin Dong
Qiang Ding
Boda Zhou
Xiaolin Tian
Haiteng Deng
Lina Xu
Xiaohui Liu
Zi Yang
Qing Chang
Jie Na
Wenwen Zeng
Giulio Superti-Furga
Manuele Rebsamen
Maojun Yang
Source :
Nature Communications, Vol 14, Iss 1, Pp 1-13 (2023)
Publication Year :
2023
Publisher :
Nature Portfolio, 2023.

Abstract

Abstract Toll-like receptors (TLRs) are a class of proteins that play critical roles in recognizing pathogens and initiating innate immune responses. TASL, a recently identified innate immune adaptor protein for endolysosomal TLR7/8/9 signaling, is recruited by the lysosomal proton-coupled amino-acid transporter SLC15A4, and then activates IRF5, which in turn triggers the transcription of type I interferons and cytokines. Here, we report three cryo-electron microscopy (cryo-EM) structures of human SLC15A4 in the apo monomeric and dimeric state and as a TASL-bound complex. The apo forms are in an outward-facing conformation, with the dimeric form showing an extensive interface involving four cholesterol molecules. The structure of the TASL-bound complex reveals an unprecedented interaction mode with solute carriers. During the recruitment of TASL, SLC15A4 undergoes a conformational change from an outward-facing, lysosomal lumen-exposed state to an inward-facing state to form a binding pocket, allowing the N-terminal helix of TASL to be inserted into. Our findings provide insights into the molecular basis of regulatory switch involving a human solute carrier and offers an important framework for structure-guided drug discovery targeting SLC15A4-TASL-related human autoimmune diseases.

Subjects

Subjects :
Science

Details

Language :
English
ISSN :
20411723
Volume :
14
Issue :
1
Database :
Directory of Open Access Journals
Journal :
Nature Communications
Publication Type :
Academic Journal
Accession number :
edsdoj.7cfd7c5510254a58a60e7826c7afde97
Document Type :
article
Full Text :
https://doi.org/10.1038/s41467-023-42210-9