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DC-SIGN signaling: Good receptor, bad receptor

Reverse-transcriptase (RT) activity of MDDC–CD4⁺ T cell cocultures of MDDCs transfected with nonspecific or LARG-specific siRNA and then exposed to HIV.

The calcium-dependent C-lectin DC-SIGN (dendritic cell-specific ICAM-3 grabbing nonintegrin) binds to mannose-containing glycoepitopes and interacts with the intercellular adhesion molecule (ICAM) on T cells to promote T cell immune responses. In addition to its role in cell adhesion, it acts as a pattern recognition receptor on dendritic cells (DCs) and modulates the function of the Toll-like receptors (TLRs). Activation of DC-SIGN was thought to stimulate intracellular signaling pathways, akin to the C-lectin Dectin-1, which signals through SYK and CARD9 to activate NF-B. However, the signaling pathways that are activated downstream of DC-SIGN have not yet been characterized. Two studies in Immunity and Nature Immunology now show that the Rho and Ras small GTPase pathways are activated following DC-SIGN binding to HIV or the mycobacterial cell wall lipoglycan ManLAM (mannose-capped lipoarabinomannan), respectively.

In their article in Immunity, Gringhuis et al. describe a link between ManLAM binding to DC-SIGN and activation of the serine/threonine kinase Raf-1. ManLAM binding to TLRs in DCs promotes expression of interleukin-10 (IL-10), and the authors observed that TLR-dependent expression of IL-10 increased when DC-SIGN was active. This effect was abolished when Raf-1 was knocked down. Expression of a dominant-negative form of Ras, as well as antibody blockage of DC-SIGN, abolished Raf-1 activation, suggesting that DC-SIGN interacts with Ras to activate Raf-1. The Raf-1 activation by DC-SIGN leads to phosphorylation and acetylation of the NF-B subunit p65. Interestingly, this can only occur after TLR-induced nuclear translocation of NF-B Acetylation of p65 leads to increased activity of NF-B, which enhances and prolongs transcription of IL-10.  Finally, the authors showed that DC-SIGN-mediated expression of IL-10 could be caused by pathogens such as M. tuberculosis, C. albicans and also HIV. As increased IL-10 expression is commonly seen in AIDS patients and can have immunosuppressive effects, inhibitors of the DC-SIGN–Ras–Raf-1–NF-B pathway could have great therapeutic value.

Another aspect of DC-SIGN in cellular signaling was described by Hodges et al. in Nature Immunology. In this study, the authors applied a proteomic approach to identify novel members of the DC-SIGN pathway, and found that HIV binding to DC-SIGN triggered Rho-GTPase activity in monocyte-derived DCs. Following DC-SIGN activation, the signaling molecule Leukemia Associated Rho Guanine nucleotide exchange factor (LARG) was phosphorylated, which in turn activated Rho-GTPase. Furthermore, all three proteins formed a complex at the cell membrane. The DC-SIGN-LARG interaction was necessary for HIV proliferation as depletion of LARG led to decreased HIV reverse transcriptase activity in DC-T cell co-cultures, indicating a reduced presence of the virus in DCs. These findings suggest that the DC-SIGN-Rho signaling pathway creates a favorable environment for viral replication.

Together, the presented results allow the hypothesis that upon binding to DC-SIGN, HIV functions similarly to ManLAM and induces cytokine responses through the Ras/Raf pathway. Thus, both reports provide profound insight into the mechanism of DC-SIGN signaling in DCs upon activation by bacterial and viral carbohydrate antigens.

Author: Mirko von Elstermann