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Galectin-3 promotes noncanonical inflammasome activation through intracellular binding to lipopolysaccharide glycans [Immunology and Inflammation]
Proceedings of the National Academy of Sciences of the United States of America ( IF 11.1 ) Pub Date : 2021-07-27 , DOI: 10.1073/pnas.2026246118
Tzu-Han Lo 1, 2, 2 , Hung-Lin Chen 2 , Cheng-I Yao 2 , I-Chun Weng 2 , Chi-Shan Li 2 , Chi-Chun Huang 2 , Nien-Jung Chen 1 , Chun-Hung Lin 2 , Fu-Tong Liu 1, 2, 2, 3
Affiliation  

Cytosolic lipopolysaccharides (LPSs) bind directly to caspase-4/5/11 through their lipid A moiety, inducing inflammatory caspase oligomerization and activation, which is identified as the noncanonical inflammasome pathway. Galectins, β-galactoside–binding proteins, bind to various gram-negative bacterial LPS, which display β-galactoside–containing polysaccharide chains. Galectins are mainly present intracellularly, but their interactions with cytosolic microbial glycans have not been investigated. We report that in cell-free systems, galectin-3 augments the LPS-induced assembly of caspase-4/11 oligomers, leading to increased caspase-4/11 activation. Its carboxyl-terminal carbohydrate-recognition domain is essential for this effect, and its N-terminal domain, which contributes to the self-association property of the protein, is also critical, suggesting that this promoting effect is dependent on the functional multivalency of galectin-3. Moreover, galectin-3 enhances intracellular LPS-induced caspase-4/11 oligomerization and activation, as well as gasdermin D cleavage in human embryonic kidney (HEK) 293T cells, and it additionally promotes interleukin-1β production and pyroptotic death in macrophages. Galectin-3 also promotes caspase-11 activation and gasdermin D cleavage in macrophages treated with outer membrane vesicles, which are known to be taken up by cells and release LPSs into the cytosol. Coimmunoprecipitation confirmed that galectin-3 associates with caspase-11 after intracellular delivery of LPSs. Immunofluorescence staining revealed colocalization of LPSs, galectin-3, and caspase-11 independent of host N-glycans. Thus, we conclude that galectin-3 amplifies caspase-4/11 oligomerization and activation through LPS glycan binding, resulting in more intense pyroptosis—a critical mechanism of host resistance against bacterial infection that may provide opportunities for new therapeutic interventions.



中文翻译:

Galectin-3 通过细胞内与脂多糖聚糖的结合促进非经典炎性体活化 [免疫学和炎症]

胞质脂多糖 (LPS) 通过其脂质 A 部分直接与 caspase-4/5/11 结合,诱导炎症性 caspase 寡聚化和活化,这被认为是非经典炎性体途径。半乳糖凝集素是一种 β-半乳糖苷结合蛋白,可与各种革兰氏阴性细菌 LPS 结合,这些 LPS 显示出含有 β-半乳糖苷的多糖链。半乳糖凝集素主要存在于细胞内,但尚未研究它们与细胞溶质微生物聚糖的相互作用。我们报告说,在无细胞系统中,galectin-3 增强了 LPS 诱导的 caspase-4/11 寡聚体组装,导致 caspase-4/11 活化增加。它的羧基末端碳水化合物识别结构域对于这种效应至关重要,它的 N 末端结构域有助于蛋白质的自缔合特性,也很关键,表明这种促进作用取决于半乳糖凝集素3的功能多价。此外,galectin-3 增强细胞内 LPS 诱导的 caspase-4/11 寡聚化和活化,以及人胚胎肾 (HEK) 293T 细胞中的 gasdermin D 裂解,它还促进巨噬细胞中 IL-1β 的产生和焦亡死亡。Galectin-3 还促进用外膜囊泡处理的巨噬细胞中的 caspase-11 活化和 gasdermin D 裂解,已知外膜囊泡被细胞吸收并将 LPS 释放到细胞质中。共免疫沉淀证实在细胞内递送 LPS 后,galectin-3 与 caspase-11 结合。免疫荧光染色显示 LPS、galectin-3 和 caspase-11 的共定位与宿主无关 galectin-3 增强细胞内 LPS 诱导的 caspase-4/11 寡聚化和活化,以及人胚胎肾 (HEK) 293T 细胞中的 gasdermin D 裂解,它还促进巨噬细胞中 IL-1β 的产生和焦亡死亡。Galectin-3 还促进用外膜囊泡处理的巨噬细胞中的 caspase-11 活化和 gasdermin D 裂解,已知外膜囊泡被细胞吸收并将 LPS 释放到细胞质中。共免疫沉淀证实在细胞内递送 LPS 后,galectin-3 与 caspase-11 结合。免疫荧光染色显示 LPS、galectin-3 和 caspase-11 的共定位与宿主无关 galectin-3 增强细胞内 LPS 诱导的 caspase-4/11 寡聚化和活化,以及人胚胎肾 (HEK) 293T 细胞中的 gasdermin D 裂解,它还促进巨噬细胞中 IL-1β 的产生和焦亡死亡。Galectin-3 还促进用外膜囊泡处理的巨噬细胞中的 caspase-11 活化和 gasdermin D 裂解,已知外膜囊泡被细胞吸收并将 LPS 释放到细胞质中。共免疫沉淀证实在细胞内递送 LPS 后,galectin-3 与 caspase-11 结合。免疫荧光染色显示 LPS、galectin-3 和 caspase-11 的共定位与宿主无关 它还促进巨噬细胞中白细胞介素 1β 的产生和焦亡死亡。Galectin-3 还促进用外膜囊泡处理的巨噬细胞中的 caspase-11 活化和 gasdermin D 裂解,已知外膜囊泡被细胞吸收并将 LPS 释放到细胞质中。共免疫沉淀证实在细胞内递送 LPS 后,galectin-3 与 caspase-11 结合。免疫荧光染色显示 LPS、galectin-3 和 caspase-11 的共定位与宿主无关 它还促进巨噬细胞中白细胞介素 1β 的产生和焦亡死亡。Galectin-3 还促进用外膜囊泡处理的巨噬细胞中的 caspase-11 活化和 gasdermin D 裂解,已知外膜囊泡被细胞吸收并将 LPS 释放到细胞质中。共免疫沉淀证实在细胞内递送 LPS 后,galectin-3 与 caspase-11 结合。免疫荧光染色显示 LPS、galectin-3 和 caspase-11 的共定位与宿主无关 共免疫沉淀证实在细胞内递送 LPS 后,galectin-3 与 caspase-11 结合。免疫荧光染色显示 LPS、galectin-3 和 caspase-11 的共定位与宿主无关 共免疫沉淀证实在细胞内递送 LPS 后,galectin-3 与 caspase-11 结合。免疫荧光染色显示 LPS、galectin-3 和 caspase-11 的共定位与宿主无关N-聚糖。因此,我们得出结论,galectin-3 通过 LPS 聚糖结合放大 caspase-4/11 寡聚化和活化,导致更强烈的细胞焦亡——这是宿主抵抗细菌感染的关键机制,可能为新的治疗干预提供机会。

更新日期:2021-07-24
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