Sweet Talking

Science Signaling  29 Sep 2009:
Vol. 2, Issue 90, pp. ec318
DOI: 10.1126/scisignal.290ec318

Pattern-recognition receptors (PRRs), such as Toll-like receptors (TLRs), enable dendritic cells (DCs) to sense a range of pathogen-associated molecular patterns from infectious organisms. Signaling from PRRs triggers the production of distinct cytokines in DCs that help to determine the T cell response to the invading pathogen. The C-type lectin DC-SIGN is a PRR on DCs that binds to mannose- or fucose-containing carbohydrates. Signaling through DC-SIGN can either enhance or inhibit TLR signaling in DC cells in a pathogen-specific manner, but the mechanisms involved are unclear. Gringhuis et al. found that, in unstimulated DCs, DC-SIGN was part of a signaling complex (signalosome) that consisted of the scaffold proteins LSP1, KSR1, and CNK1. These proteins were required for the constitutive recruitment of the kinase Raf1 to DC-SIGN. Mannose-containing ligands or mannose-bearing pathogens stimulated the recruitment to the signalosome of upstream molecules, including RhoA and the guanine nucleotide exchange factor LARG, that resulted in the activation of Raf1. This process was required for the mannose-dependent enhancement of TLR4-dependent cytokine production in DCs in response to lipopolysaccharide (LPS). In contrast, fucose-containing ligands or fucose-bearing pathogens inhibited the production of most of the cytokines induced by LPS, and this effect was independent of the activity of Raf1. In addition, binding of fucose-containing ligands to DC-SIGN disrupted the signalosome such that only LSP1 still bound to DC-SIGN. The authors suggest that binding of different carbohydrate moieties may induce specific conformational changes in DC-SIGN that determine which signalosomes are made. Together, these data suggest that a single PRR can modulate its responses to multiple ligands by assembling distinct signaling complexes and thus differentially affect signaling from other PRRs.

S. I. Gringhuis, J. den Dunnen, M. Litjens, M. van der Vlist, T. B. H. Geijtenbeek, Carbohydrate-specific signaling through the DC-SIGN signalosome tailors immunity to Mycobacterium tuberculosis, HIV-1 and Helicobacter pylori. Nat. Immunol. 10, 1081–1088 (2009). [PubMed]