Structural basis for recruitment of TASL by SLC15A4 in human endolysosomal TLR signaling
Xudong Chen, Min Xie, Sensen Zhang, Marta Tortajada, Jian Yin, Chang Liu, Youqi Zhang, Maeva Delacrétaz, Mingyue Song, Yixue Wang, Dong Lin, 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
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.