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- Title
Structural basis for recruitment of TASL by SLC15A4 in human endolysosomal TLR signaling.
- Authors
Chen, Xudong; Xie, Min; Zhang, Sensen; Monguió-Tortajada, Marta; Yin, Jian; Liu, Chang; Zhang, Youqi; Delacrétaz, Maeva; Song, Mingyue; Wang, Yixue; Dong, Lin; Ding, Qiang; Zhou, Boda; Tian, Xiaolin; Deng, Haiteng; Xu, Lina; Liu, Xiaohui; Yang, Zi; Chang, Qing; Na, Jie
- 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. Three structures of human SLC15A4 are presented in the outward-facing apo monomeric and dimeric states and the inward-facing TASL-bound state, revealing the molecular mechanism of SLC15A4-mediated TASL recruitment in human endolysosomal TLRs signalling.
- Subjects
TYPE I interferons; DRUG discovery; TOLL-like receptors
- Publication
Nature Communications, 2023, Vol 14, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-023-42210-9