Activation of the lectin DC-SIGN induces an immature dendritic cell phenotype triggering Rho-GTPase activity required for HIV-1 replication.
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.
Hodges
Ashleigh
A
Medical Research Council Human Immunology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Headington, Oxford OX3 9DS, UK.
Sharrocks
Katherine
K
Edelmann
Mariola
M
Baban
Dilair
D
Moris
Arnaud
A
Schwartz
Olivier
O
Drakesmith
Hal
H
Davies
Kay
K
Kessler
Benedikt
B
McMichael
Andrew
A
Simmons
Alison
A
D000595:Amino Acid Sequence; D015815:Cell Adhesion Molecules / Q000276:immunology*; D002454:Cell Differentiation; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000166:cytology / Q000201:enzymology* / Q000276:immunology*; D004789:Enzyme Activation; D020869:Gene Expression Profiling; D020662:Guanine Nucleotide Exchange Factors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D015497:HIV-1 / Q000502:physiology*; D006801:Humans; D037181:Lectins, C-Type / Q000276:immunology*; D008969:Molecular Sequence Data; D010641:Phenotype; D010768:Phosphoserine / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000276:immunology*; D064067:Rho Guanine Nucleotide Exchange Factors; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D014158:Transcription, Genetic / Q000235:genetics; D014779:Virus Replication; D020741:rho GTP-Binding Proteins / Q000378:metabolism*; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin
D015815:Cell Adhesion Molecules; D020662:Guanine Nucleotide Exchange Factors; D037181:Lectins, C-Type; D010768:Phosphoserine; D011956:Receptors, Cell Surface; D064067:Rho Guanine Nucleotide Exchange Factors; D020741:rho GTP-Binding Proteins; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin; C577222:ARHGEF12 protein, human