Bi Shuguang, Earl Lesley A, Jacobs Linsey, Baum Linda G
Department of Pathology and Laboratory Medicine, UCLA School of Medicine, Los Angeles, California 90095, USA.
J Biol Chem. 2008 May 2;283(18):12248-58. doi: 10.1074/jbc.M800523200. Epub 2008 Feb 7.
The galectin family of lectins regulates multiple biologic functions, such as development, inflammation, immunity, and cancer. One common function of several galectins is the ability to trigger T cell death. However, differences among the death pathways triggered by various galectins with regard to glycoprotein receptors, intracellular death pathways, and target cell specificity are not well understood. Specifically, galectin-9 and galectin-1 both kill thymocytes, peripheral T cells, and T cell lines; however, we have found that galectin-9 and galectin-1 require different glycan ligands and glycoprotein receptors to trigger T cell death. The two galectins also utilize different intracellular death pathways, as galectin-9, but not galectin-1, T cell death was blocked by intracellular Bcl-2, whereas galectin-1, but not galectin-9, T cell death was blocked by intracellular galectin-3. Target cell susceptibility also differed between the two galectins, as galectin-9 and galectin-1 killed different subsets of murine thymocytes. To define structural features responsible for distinct activities of the tandem repeat galectin-9 and dimeric galectin-1, we created a series of bivalent constructs with galectin-9 and galectin-1 carbohydrate recognition domains connected by different peptide linkers. We found that the N-terminal carbohydrate recognition domain and linker peptide contributed to the potency of these constructs. However, we found that the C-terminal carbohydrate recognition domain was the primary determinant of receptor recognition, death pathway signaling, and target cell susceptibility. Thus, carbohydrate recognition domain specificity, presentation, and valency make distinct contributions to the specific effects of different galectins in initiating T cell death.
半乳糖凝集素家族的凝集素调节多种生物学功能，如发育、炎症、免疫和癌症。几种半乳糖凝集素的一个共同功能是触发T细胞死亡的能力。然而，对于各种半乳糖凝集素触发的死亡途径在糖蛋白受体、细胞内死亡途径和靶细胞特异性方面的差异，人们还了解得不够清楚。具体而言，半乳糖凝集素-9和半乳糖凝集素-1都能杀死胸腺细胞、外周T细胞和T细胞系；然而，我们发现半乳糖凝集素-9和半乳糖凝集素-1需要不同的聚糖配体和糖蛋白受体来触发T细胞死亡。这两种半乳糖凝集素还利用不同的细胞内死亡途径，因为半乳糖凝集素-9（而非半乳糖凝集素-1）诱导的T细胞死亡可被细胞内的Bcl-2阻断，而半乳糖凝集素-1（而非半乳糖凝集素-9）诱导的T细胞死亡可被细胞内的半乳糖凝集素-3阻断。两种半乳糖凝集素在靶细胞易感性方面也存在差异，因为半乳糖凝集素-9和半乳糖凝集素-1杀死的是小鼠胸腺细胞的不同亚群。为了确定负责串联重复的半乳糖凝集素-9和二聚体半乳糖凝集素-1不同活性的结构特征，我们构建了一系列二价构建体，将半乳糖凝集素-9和半乳糖凝集素-1的碳水化合物识别结构域通过不同的肽接头连接起来。我们发现N端碳水化合物识别结构域和接头肽对这些构建体的效力有贡献。然而，我们发现C端碳水化合物识别结构域是受体识别、死亡途径信号传导和靶细胞易感性的主要决定因素。因此，碳水化合物识别结构域的特异性、呈现方式和价态对不同半乳糖凝集素启动T细胞死亡的特定效应有不同的贡献。
