Endosomes are specialized platforms for bacterial sensing and NOD2 signalling

Abstract

The detection of microbial pathogens involves the recognition of conserved microbial components by host cell sensors such as Toll-like receptors (TLRs) and NOD-like receptors (NLRs). TLRs are membrane receptors that survey the extracellular environment for microbial infections, whereas NLRs are cytosolic complexes that detect microbial products that reach the cytosol. Upon detection, both sensor classes trigger innate inflammatory responses and allow the engagement of adaptive immunity. Endo-lysosomes are the entry sites for a variety of pathogens, and therefore the sites at which the immune system first senses their presence. Pathogens internalized by endocytosis are well known to activate TLRs 3 and 7-9 that are localized to endocytic compartments and detect ligands present in the endosomal lumen. Internalized pathogens also activate sensors in the cytosol such as NOD1 and NOD2 (ref. 2), indicating that endosomes also provide for the translocation of bacterial components across the endosomal membrane. Despite the fact that NOD2 is well understood to have a key role in regulating innate immune responses and that mutations at the NOD2 locus are a common risk factor in inflammatory bowel disease and possibly other chronic inflammatory states, little is known about how its ligands escape from endosomes. Here we show that two endo-lysosomal peptide transporters, SLC15A3 and SLC15A4, are preferentially expressed by dendritic cells, especially after TLR stimulation. The transporters mediate the egress of bacterially derived components, such as the NOD2 cognate ligand muramyl dipeptide (MDP), and are selectively required for NOD2 responses to endosomally derived MDP. Enhanced expression of the transporters also generates endosomal membrane tubules characteristic of dendritic cells, which further enhanced the NOD2-dependent response to MDP. Finally, sensing required the recruitment of NOD2 and its effector kinase RIPK2 (refs 8, 9) to the endosomal membrane, possibly by forming a complex with SLC15A3 or SLC15A4. Thus, dendritic cell endosomes are specialized platforms for both the lumenal and cytosolic sensing of pathogens.

NOD-Like Receptors: Versatile Cytosolic Sentinels

“…This study concluded that NOD1 ligands require further processing by endosomal enzymes prior to cytosolic entry and identified SLC15A4 as the likely endosomal oligopeptide transporter (158). A recent study confirmed these findings and also suggested a role for SLC15A3 in this process (210). Finally, in vivo studies have also supported these findings, as SCL15A4-deficient mice were impaired in NOD1-dependent cytokine production, suggesting that NOD1 ligand entry occurs through SLC15A4 (249).…”

Cutting Edge: New Chimeric NOD2/TLR2 Adjuvant Drastically Increases Vaccine Immunogenicity

“…We hypothesized that the chimera is taken up through its TLR2 agonist domain in lipid rafts and internalized within endosomes (19,20), enabling more NOD2 ligands to enter the cells. How the NOD2 agonist domain of the chimera interacts with the NOD2 receptor after endosomal internalization is still beyond our comprehension and requires further study, but involvement of the SLC15A3 and SLC15A4 transporters seems to be crucial (21,22).…”

Innate immunity in diabetes and diabetic nephropathy

“…Another set of intracellular sensing PRRs are NLRs, which are localized in the cytosol and are essential for sensing invading pathogens and prompting the innate immune response 20 .…”