Department of Biological Sciences, University of North Carolina, Charlotte, NC, USA.
Department of Biochemistry, Medical College of Wisconsin, Milwaukee, WI, USA.
Sci Rep. 2022 Oct 13;12(1):17204. doi: 10.1038/s41598-022-21651-0.
Chemokines form a family of proteins with critical roles in many biological processes in health and disease conditions, including cardiovascular, autoimmune diseases, infections, and cancer. Many chemokines engage in heterophilic interactions to form heterodimers, leading to synergistic activity enhancement or reduction dependent on the nature of heterodimer-forming chemokines. In mixtures, different chemokine species with diverse activities coexist in dynamic equilibrium, leading to the observation of their combined response in biological assays. To overcome this problem, we produced a non-dissociating CXCL4-CXCL12 chemokine heterodimer OHD as a new tool for studying the biological activities and mechanisms of chemokine heterodimers in biological environments. Using the OHD, we show that the CXCL4-CXCL12 chemokine heterodimer inhibits the CXCL12-driven migration of triple-negative MDA-MB-231 breast cancer cells. We also show that the CXCL4-CXCL12 chemokine heterodimer binds and activates the CXCR4 receptor.
趋化因子是一类在健康和疾病条件下的许多生物学过程中发挥关键作用的蛋白质家族，包括心血管、自身免疫性疾病、感染和癌症。许多趋化因子通过形成异源二聚体进行异亲相互作用，导致协同活性增强或减弱，这取决于形成异源二聚体的趋化因子的性质。在混合物中，不同活性的趋化因子物种以动态平衡的方式共存，导致在生物测定中观察到它们的联合反应。为了解决这个问题，我们生产了一种非解离的 CXCL4-CXCL12 趋化因子异源二聚体 OHD，作为研究生物环境中趋化因子异源二聚体的生物学活性和机制的新工具。使用 OHD，我们表明 CXCL4-CXCL12 趋化因子异源二聚体抑制 CXCL12 驱动的三阴性 MDA-MB-231 乳腺癌细胞的迁移。我们还表明，CXCL4-CXCL12 趋化因子异源二聚体结合并激活 CXCR4 受体。
