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

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 and Maojun Yang ()
Additional contact information
Xudong Chen: Tsinghua University
Min Xie: Tsinghua University
Sensen Zhang: Tsinghua University
Marta Monguió-Tortajada: University of Lausanne
Jian Yin: Tsinghua University
Chang Liu: Tsinghua University
Youqi Zhang: Beijing Key Laboratory of Kidney Disease Research
Maeva Delacrétaz: University of Lausanne
Mingyue Song: Tsinghua University
Yixue Wang: Tsinghua University
Lin Dong: Tsinghua University
Qiang Ding: Tsinghua University
Boda Zhou: Tsinghua University
Xiaolin Tian: Tsinghua University
Haiteng Deng: Tsinghua University
Lina Xu: Tsinghua University
Xiaohui Liu: Tsinghua University
Zi Yang: Tsinghua University
Qing Chang: Tsinghua University
Jie Na: Tsinghua University
Wenwen Zeng: Tsinghua University
Giulio Superti-Furga: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences
Manuele Rebsamen: University of Lausanne
Maojun Yang: Tsinghua University

Nature Communications, 2023, vol. 14, issue 1, 1-13

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.

Date: 2023
References: View references in EconPapers View complete reference list from CitEc
Citations: View citations in EconPapers (1)

Downloads: (external link)
https://www.nature.com/articles/s41467-023-42210-9 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-42210-9

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-023-42210-9

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().