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Immunity. 2015 Nov 17;43(5):909-22. doi: 10.1016/j.immuni.2015.10.008. Epub 2015 Nov 3.

Mechanisms of Toll-like Receptor 4 Endocytosis Reveal a Common Immune-Evasion Strategy Used by Pathogenic and Commensal Bacteria.

Author information

1
Harvard Medical School and Division of Gastroenterology, Boston Children's Hospital, Boston, MA 02115, USA.
2
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.
3
Department of Microbial Pathogenesis and Microbial Sciences Institute, Yale University School of Medicine, New Haven, CT 06520, USA.
4
Harvard Medical School and Division of Gastroenterology, Boston Children's Hospital, Boston, MA 02115, USA. Electronic address: jonathan.kagan@childrens.harvard.edu.

Abstract

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.

PMID:
26546281
PMCID:
PMC4685471
DOI:
10.1016/j.immuni.2015.10.008
[Indexed for MEDLINE]
Free PMC Article

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