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

Chen，Xudong1; Xie，Min2; Zhang，Sensen1; Monguió-Tortajada，Marta3; Yin，Jian1; Liu，Chang1,4; Zhang，Youqi5; Delacrétaz，Maeva3; Song，Mingyue1; Wang，Yixue1; Dong，Lin6; Ding，Qiang6; Zhou，Boda7; Tian，Xiaolin8; Deng，Haiteng8; Xu，Lina9; Liu，Xiaohui9; Yang，Zi10; Chang，Qing10; Na，Jie2; Zeng，Wenwen2; Superti-Furga，Giulio11,12; Rebsamen，Manuele3; Yang，Maojun1,13

2023-12-01

10.1038/s41467-023-42210-9

Nature Communications   影响因子和分区

2041-1723

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.

SCI

英语

NI论文

通讯

2-s2.0-85174519517

Scopus

1.Ministry of Education Key Laboratory of Protein Science,Tsinghua-Peking Center for Life Sciences,Beijing Advanced Innovation Center for Structural Biology,School of Life Sciences,Tsinghua University,Beijing,100084,China
2.School of Medicine,Tsinghua University,Beijing,100084,China
3.Department of Immunobiology,University of Lausanne,Epalinges,1066,Switzerland
4.Beijing Life Science Academy,Beijing,102209,China
5.Department of Nephrology,First Medical Center of Chinese PLA General Hospital,Nephrology Institute of the Chinese People’s Liberation Army,National Key Laboratory of Kidney Diseases,National Clinical Research Center for Kidney Diseases,Beijing Key Laboratory of Kidney Disease Research,Beijing,100853,China
6.Center for Infectious Disease Research,School of Medicine,Tsinghua University,Beijing,100084,China
7.Department of Cardiology,Beijing Tsinghua Changgung Hospital,School of Clinical Medicine,Tsinghua University,Beijing,102218,China
8.MOE Key laboratory of Bioinformatics,School of Life Sciences,Tsinghua University,Beijing,100084,China
9.Metabolomics and Lipidomics Center at Tsinghua—National Protein Science Facility,School of Life Sciences,Tsinghua University,Beijing,100084,China
10.Beijing Advanced Innovation Center for Structural Biology,Technology for Protein Research,School of Life Sciences,Tsinghua University,Beijing,100084,China
11.CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences,Vienna,Austria
12.Center for Physiology and Pharmacology,Medical University of Vienna,Vienna,Austria
13.Cryo-EM Facility Center,Southern University of Science & Technology,Shenzhen,Guangdong,518055,China

Chen，Xudong,Xie，Min,Zhang，Sensen,et al. Structural basis for recruitment of TASL by SLC15A4 in human endolysosomal TLR signaling[J]. Nature Communications,2023,14(1).

Chen，Xudong.,Xie，Min.,Zhang，Sensen.,Monguió-Tortajada，Marta.,Yin，Jian.,...&Yang，Maojun.(2023).Structural basis for recruitment of TASL by SLC15A4 in human endolysosomal TLR signaling.Nature Communications,14(1).

Chen，Xudong,et al."Structural basis for recruitment of TASL by SLC15A4 in human endolysosomal TLR signaling".Nature Communications 14.1(2023).