Development of conformation-selective antibodies targeting human SLC15A4

Yalan Zhu, Xuyuan Zhang, Qixiang Zhang, Panpan Sun, Kexin Liu, Xiaohua Nie, Junxiao Ma, Liwei Zhang, Yina Gao, Yong Wang, Songqing Liu, Ang Gao (), Liguo Zhang () and Pu Gao ()
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Yalan Zhu: Beijing Institute of Technology
Xuyuan Zhang: Chinese Academy of Sciences
Qixiang Zhang: Beijing Institute of Technology
Panpan Sun: Chinese Academy of Sciences
Kexin Liu: Chinese Academy of Sciences
Xiaohua Nie: Chinese Academy of Sciences
Junxiao Ma: Chinese Academy of Sciences
Liwei Zhang: Chinese Academy of Sciences
Yina Gao: Chinese Academy of Sciences
Yong Wang: Chinese Academy of Sciences
Songqing Liu: Chinese Academy of Sciences
Ang Gao: Beijing Institute of Technology
Liguo Zhang: Chinese Academy of Sciences
Pu Gao: Chinese Academy of Sciences

Nature Communications, 2025, vol. 16, issue 1, 1-13

Abstract: Abstract SLC15A4, an endolysosomal solute carrier family transporter, plays a critical role in TLR7/8/9-induced immune responses through assembling a complex with the downstream adaptor TASL in a conformation-dependent manner. Despite its close functional association and promising therapeutic potential in infections, tumors, and autoimmune diseases, the development of conformation-specific antibodies for human SLC15A4 (hSLC15A4) remains challenging. Here, using a systematic screening and validation approach, we identify a pair of conformation-selective antibodies, clones 107 and 235, targeting the endolysosomal lumen surface of hSLC15A4 with opposite conformation-regulatory activities. Specifically, clone 107 selectively binds to hSLC15A4 in a TASL binding-incompetent luminal-open state; whereas clone 235 stabilizes hSLC15A4 in a TASL binding-competent cytoplasmic-open state. Our research identifies antibodies that recognize distinct conformations of hSLC15A4, potentially enabling modulation of the TLR7/8/9 pathway and contributing to the development of targeted therapies and research tools selectively targeting hSLC15A4.

Date: 2025
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DOI: 10.1038/s41467-025-62759-x

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