Activation of the lectin DC-SIGN induces an immature dendritic cell phenotype triggering Rho-GTPase activity required for HIV-1 replication

Medical Research Council Human Immunology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Headington, Oxford OX3 9DS, UK.
Nature Immunology (Impact Factor: 24.97). 07/2007; 8(6):569-77. DOI: 10.1038/ni1470
Source: PubMed

ABSTRACT DC-SIGN, a C-type lectin expressed on dendritic cells (DCs), can sequester human immunodeficiency virus (HIV) virions in multivesicular bodies. Here, using large-scale gene expression profiling and tyrosine-phosphorylated proteome analyses, we characterized signaling mediated by DC-SIGN after activation by either HIV or a DC-SIGN-specific antibody. Activation of DC-SIGN resulted in downregulation of genes encoding major histocompatibility complex class II, Jagged 1 and interferon-response molecules and upregulation of the gene encoding transcription factor ATF3. Phosphorylated proteome analysis showed that HIV- or antibody-stimulated DC-SIGN signaling was mediated by the Rho guanine nucleotide-exchange factor LARG and led to increased Rho-GTPase activity. Activation of LARG in DCs exposed to HIV was required for the formation of virus-T cell synapses. Thus, HIV sequestration by and stimulation of DC-SIGN helps HIV evade immune responses and spread to cells.

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Available from: Benedikt M Kessler, May 28, 2014
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    • "Engagement of HIV-1 Env to DC-SIGN or DCIR can induce phosphorylation of corresponding CLR in its cytoplasmic tail, consequently activating a signal transduction pathway that contributes to HIV-1 immune evasion, productive proliferation and infection (Gringhuis et al., 2010; Lambert et al., 2011; Sarkar et al., 2013). For instance, activation of DC-SIGN induces an immature dendritic cell phenotype triggering Rho-GTPase activity required for HIV-1 replication (Hodges et al., 2007). Furthermore, the ITIMassociated signal transduction pathway of DCIR has also been reported to enhance HIV-1 infection, and probably also affect the immune response of HIV-1. "
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    • "There have been no reports of a mechanism for DC-SIGN mediated phagocytosis. However, activation of DC-SIGN triggers Rho-GTPase (Hodges et al., 2007) making it conceivable that Rho could be involved in phagocytosis mediated by this receptor. "
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    • "DC-specific intracellular adhesion molecule-3 grabbing non-integrin (DC-SIGN) is a member of the CLR family and expressed on DCs present at mucosal sites, as well as skin, and lymph nodes (Geijtenbeek et al., 2000a). DC-SIGN specifically binds high-mannose glycans and Lewis-type antigens (Appelmelk et al., 2003; van Liempt et al., 2006; Mitchell et al., 2001) which are present on pathogens such as HIV (Geijtenbeek et al., 2000b; Hodges et al., 2007) and Mycobacterium (Geijtenbeek et al., 2003). DC-SIGN recognizes carbohydrate structures through its carbohydrate recognition domain (CRD) in a Ca 2+ -dependent fashion (Geijtenbeek et al., 2000a). "
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