C-type lectin DC-SIGN: an adhesion, signalling and antigen-uptake molecule that guides dendritic cells in immunity

Abstract

The dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin (DC-SIGN) is a type II C-type lectin whose expression is restricted to the most potent antigen-presenting cells (APCs), the dendritic cells (DCs). In recent years, DC-SIGN has gained an exponential increase in attention because of its involvement in multiple aspects of immune function. Besides being an adhesion molecule, particularly in binding ICAM-2 and ICAM-3, it is also crucial in recognizing several endogenous and exogenous antigens. Additionally, the intracellular domain of DC-SIGN includes molecular motifs, which enable the activation of signal transduction pathways involving Raf-1 and subsequent modulation of DC-maturation status, through direct modification of nuclear factor Nf-kappaB in DCs. Upon DC-SIGN engagement by mannose- or fucose-containing oligosaccharides, the latter leads to a tailored Toll-like receptor signalling, resulting in an altered DC-cytokine profile and skewing of Th1/Th2 responses. In this article, we will discuss recent advances on a broad perspective concerning DC-SIGN structure, signalling and immune function.

Fig. 1

a. Schematic structure of DC-SIGN and amino-acid sequence alignment of the neck-repeat domain. The repeated hydrophobic amino-acid residues (hydrophobic heptad), crucial for tetramerization, is highlighted. Arrows point to the subtilisin site of digestion. b. DC-SIGN tetramerization through hydrophobic residues stacking in the neck-repeat domain (modified from Feinberg et al. [26]).

Fig. 2

DC-SIGN signalling is ligand-dependent, activates Raf and down-stream mediators and contributes to modulation of signalling involved in DC activation. Activation of DC-SIGN with ManLam or gp120 leads to increased phosphorylation of Raf-1. This process requires a conformational change in Raf-1, that is mediated by small GTPase Ras. Raf-1 can then be phosphorylated at Ser338 by p21-activated kinases (Pak) and at Tyr340 and Tyr341 by kinases belonging to Src family, most probably Lyn and Syk. Activated Raf-1 is neccessary for phosphorylation of p50/p65 Nf-κB dimer in the nucleus, which is a prerequisite for later Nf-κB modification by histone acetyltransferases (HATs). The acetylation of Nf-κB is carried out at lysine residues 221 and 310 and this enables increased DNA binding and transcriptional activity by Nf-κB, leading to up-regulated IL-10 production. Salp15 binding to DC-SIGN leads to Raf-1 activation and modulated cytokine production without modulation of Nf-κB. In this manner, Raf-1 activates MEK, which without the activity of ERK, leads to increased degradation of IL-6 and TNF-α mRNA, as well as nucleosome remodelling at the IL-12p35 promoter.

Fig. 3

HIV-1 interaction with DC-SIGN and subsequent events. The first CD4⁺ T-cell infection pathway through an HIV-1 escape mechanism is depicted with red arrows; an alternative 2nd pathway through DC infection is depicted with green arrows. Both pathways merge in HIV-1 trans transfer to CD4⁺ cells. DC-SIGN signalling modulation is presented in acid green.