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.

Authors in the journal Immunity 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.

Their analysis of LPS variants from human pathogens and gut commensals revealed a common mechanism by which bacteria prevent inflammatory endocytosis.

They 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.

http://www.cell.com/immunity/abstract/S1074-7613(15)00408-2