Tan Yunhao, Zanoni Ivan, Cullen Thomas W, Goodman Andrew L, Kagan Jonathan C
Harvard Medical School and Division of Gastroenterology, Boston Children's Hospital, Boston, MA 02115, USA.
Harvard Medical School and Division of Gastroenterology, Boston Children's Hospital, Boston, MA 02115, USA; Department of Biotechnology and Biosciences, University of Milano-Bicocca, Milan 20126, Italy; Unit of Cell Signalling and Innate Immunity, Humanitas Clinical and Research Center, Rozzano 20089, Italy.
Immunity. 2015 Nov 17;43(5):909-22. doi: 10.1016/j.immuni.2015.10.008. Epub 2015 Nov 3.
Microbe-induced receptor trafficking has emerged as an essential means to promote innate immune signal transduction. Upon detection of bacterial lipopolysaccharides (LPS), CD14 induces an inflammatory endocytosis pathway that delivers Toll-like receptor 4 (TLR4) to endosomes. Although several regulators of CD14-dependent TLR4 endocytosis have been identified, the cargo-selection mechanism during this process remains unknown. We reveal that, in contrast to classic cytosolic interactions that promoted the endocytosis of transmembrane receptors, TLR4 was selected as cargo for inflammatory endocytosis entirely through extracellular interactions. Mechanistically, the extracellular protein MD-2 bound to and dimerized TLR4 in order to promote this endocytic event. Our analysis of LPS variants from human pathogens and gut commensals revealed a common mechanism by which bacteria prevent inflammatory endocytosis. We suggest that evasion of CD14-dependent endocytosis is an attribute that transcends the concept of pathogenesis and might be a fundamental feature of bacteria that inhabit eukaryotic hosts.
微生物诱导的受体转运已成为促进先天免疫信号转导的重要手段。在检测到细菌脂多糖（LPS）后，CD14会诱导一条炎症性内吞途径，将Toll样受体4（TLR4）转运至内体。尽管已经鉴定出几种依赖CD14的TLR4内吞作用的调节因子，但这一过程中的货物选择机制仍然未知。我们发现，与促进跨膜受体内吞作用的经典胞质相互作用不同，TLR4完全通过细胞外相互作用被选为炎症性内吞作用的货物。从机制上讲，细胞外蛋白MD-2与TLR4结合并使其二聚化，以促进这一内吞事件。我们对来自人类病原体和肠道共生菌的LPS变体的分析揭示了细菌阻止炎症性内吞作用的共同机制。我们认为，逃避依赖CD14的内吞作用是一种超越发病机制概念的特性，可能是栖息在真核宿主中的细菌的一个基本特征。
