Albers Dan Pascal Jean, Novikova Sofya, Vieyto-Nuñez Julio, Almeida-Hernández Yasser, Pastorio Chiara, Klassen Florian, Weiss Dana, von Maltitz Pascal, Jaikishan Janeni, Datta Moumita, Jumaa Hassan, Jebaraj Billy Michael Chelliah, Stilgenbauer Stephan, Kumar Manish, Maity Palash Chandra, Buske Christian, Stifel Ulrich, Zinngrebe Julia, Fischer-Posovszky Pamela, Chevigné Andy, Kirchhoff Frank, Sanchez-Garcia Elsa, Münch Jan, Harms Mirja
Institute of Molecular Virology, Ulm University Medical Center, 89081, Ulm, Germany.
Chair of Computational Bioengineering, Department of Biochemical and Chemical Engineering, Technical University Dortmund, 44227, Dortmund, Germany.
Cell Commun Signal. 2025 May 20;23(1):234. doi: 10.1186/s12964-025-02231-x.
GPR15LG, a chemokine-like ligand for the G-protein coupled receptor 15 (GPR15), is abundantly expressed in the gastrointestinal mucosa and inflamed skin. Emerging evidence suggests its involvement in inflammatory disorders and cancers. C-X-C chemokine receptor type 4 (CXCR4) plays a critical role in immune cell trafficking and cancer metastasis. Recent evidence suggests a connection between GPR15LG and CXCR4 signaling, which has not been investigated so far.
We investigated the effects of GPR15LG on CXCR4 signaling and downstream functions. Binding assays and computational modeling were performed to assess the interaction between GPR15LG and CXCR4. Functional assays, including wound healing and cell migration assays, were conducted across various cell types, including CD4⁺ T cells and cancer cells, to evaluate the impact of GPR15LG on CXCL12-mediated CXCR4 signaling.
The results demonstrate that GPR15LG binds to the orthosteric site of CXCR4, modulating downstream signaling in a context-dependent manner. Specifically, GPR15LG enhances CXCL12-mediated CXCR4 signaling synergistically, promoting wound healing and cell migration across various cell types, including CD4 + T cells and cancer cells.
These findings underscore the role of GPR15LG in inflammation and metastasis, offering potential therapeutic avenues for CXCR4-mediated diseases.
GPR15LG是G蛋白偶联受体15（GPR15）的一种趋化因子样配体，在胃肠道黏膜和炎症皮肤中大量表达。新出现的证据表明其参与炎症性疾病和癌症。C-X-C趋化因子受体4型（CXCR4）在免疫细胞运输和癌症转移中起关键作用。最近的证据表明GPR15LG与CXCR4信号传导之间存在联系，而这一点迄今尚未得到研究。
我们研究了GPR15LG对CXCR4信号传导和下游功能的影响。进行结合试验和计算建模以评估GPR15LG与CXCR4之间的相互作用。在包括CD4⁺T细胞和癌细胞在内的多种细胞类型中进行了功能试验，包括伤口愈合和细胞迁移试验，以评估GPR15LG对CXCL12介导的CXCR4信号传导的影响。
结果表明，GPR15LG与CXCR4的正构位点结合，以上下文依赖的方式调节下游信号传导。具体而言，GPR15LG协同增强CXCL12介导的CXCR4信号传导，促进包括CD4⁺T细胞和癌细胞在内的多种细胞类型的伤口愈合和细胞迁移。
这些发现强调了GPR15LG在炎症和转移中的作用，为CXCR4介导的疾病提供了潜在的治疗途径。
