Abstract
As pattern recognition receptor on dendritic cells (DCs), DC-SIGN binds carbohydrate structures on its pathogen ligands and essentially determines host pathogen interactions because it both skews T cell responses and enhances pathogen uptake for cis infection and/or T cell trans-infection. How these processes are initiated at the plasma membrane level is poorly understood. We now show that DC-SIGN ligation on DCs by antibodies, mannan or measles virus (MV) causes rapid activation of neutral and acid sphingomyelinases followed by accumulation of ceramides in the outer membrane leaflet. SMase activation is important in promoting DC-SIGN signaling, but also for enhancement of MV uptake into DCs. DC-SIGN-dependent SMase activation induces efficient, transient recruitment of CD150, which functions both as MV uptake receptor and microbial sensor, from an intracellular Lamp-1+ storage compartment shared with acid sphingomyelinase (ASM) within a few minutes. Subsequently, CD150 is displayed at the cell surface and co-clusters with DC-SIGN. Thus, DC-SIGN ligation initiates SMase-dependent formation of ceramide-enriched membrane microdomains which promote vertical segregation of CD150 from intracellular storage compartments along with ASM. Given the ability to promote receptor and signalosome co-segration into (or exclusion from) ceramide enriched microdomains which provide a favorable environment for membrane fusion, DC-SIGN-dependent SMase activation may be of general importance for modes and efficiency of pathogen uptake into DCs, and their routing to specific compartments, but also for modulating T cell responses.
Highlights
Their interaction with myeloid dendritic cells (DCs) is believed to be central to the understanding of immunomodulation by viruses including measles virus [1,2,3,4]
DC-SIGN may act to trap or concentrate virions for receptor interaction, and we analysed whether measles virus (MV) interaction with this molecule promoted membrane ceramide accumulation on DCs by employing an assay based on immunodetection of an aceramide antibody bound to intact cells
Their location in the mucosa coins them first cells encountering invading pathogens including viruses which, occasionally, exploit these cells as Trojan horses for transfer to secondary lymphoid tissues. They display a plethora of pattern recognition receptors (PRRs), and amongst those, the C-type lectin receptor DC-SIGN containing a mannosebinding domain has received particular attention with regard to its extraordinary pathogen–recognition capability which involves a broad panel of microorganisms and viruses including HIV and MV
Summary
Their interaction with myeloid dendritic cells (DCs) is believed to be central to the understanding of immunomodulation by viruses including measles virus [1,2,3,4]. DC-SIGN is a C-type lectin receptor which functions to regulate adhesion by interaction with integrins, and, as a pattern recognition receptor (PRR), to recognize carbohydrate structures on pathogens, thereby targeting them for endocytic uptake, processing and subsequent presentation [13,14,15]. It is enriched in nanoclusters at the leading edge on the DC plasma membrane, where ligands are acquired and transported rearward to mid-lamellar sites for subsequent endocytosis [16,17,18,19]. DC-SIGN-induced Raf-1 kinase activation was linked to modulation of TLR signaling at the level of NF-kB activation by promoting activation of its p65 subunit and thereby increasing initiation and duration of cytokine gene transcription [11,21,22]
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