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Development of conformation-selective antibodies targeting human SLC15A4.

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Titel: Development of conformation-selective antibodies targeting human SLC15A4.
Autoren: Zhu, Yalan, Zhang, Xuyuan, Zhang, Qixiang, Sun, Panpan, Liu, Kexin, Nie, Xiaohua, Ma, Junxiao, Zhang, Liwei, Gao, Yina, Wang, Yong, Liu, Songqing, Gao, Ang, Zhang, Liguo, Gao, Pu
Quelle: Nature Communications; 8/8/2025, Vol. 16 Issue 1, p1-13, 13p
Schlagwörter: IMMUNE response, TOLL-like receptors, PROTEINS, CONFORMATIONAL analysis, TREATMENT effectiveness, IMMUNOGLOBULINS, THERAPEUTICS, MEMBRANE proteins
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. SLC15A4 is essential for TLR7/8/9-mediated immune responses through a conformation-dependent interaction with TASL. Here, the authors identify two conformation-selective antibodies that differentially target distinct structural states of human SLC15A4. [ABSTRACT FROM AUTHOR]
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Datenbank: Complementary Index
Beschreibung
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. SLC15A4 is essential for TLR7/8/9-mediated immune responses through a conformation-dependent interaction with TASL. Here, the authors identify two conformation-selective antibodies that differentially target distinct structural states of human SLC15A4. [ABSTRACT FROM AUTHOR]
ISSN:20411723
DOI:10.1038/s41467-025-62759-x