C-type lectin DC-SIGN modulates Toll-like receptor signaling via Raf-1 kinase-dependent acetylation of transcription factor NF-kappaB

Sonja I Gringhuis, Jeroen den Dunnen, Manja Litjens, Bert van Het Hof, Yvette van Kooyk, Teunis B H Geijtenbeek

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Adaptive immune responses by dendritic cells (DCs) are critically controlled by Toll-like receptor (TLR) function. Little is known about modulation of TLR-specific signaling by other pathogen receptors. Here, we have identified a molecular signaling pathway induced by the C-type lectin DC-SIGN that modulates TLR signaling at the level of the transcription factor NF-kappaB. We demonstrated that pathogens trigger DC-SIGN on human DCs to activate the serine and threonine kinase Raf-1, which subsequently leads to acetylation of the NF-kappaB subunit p65, but only after TLR-induced activation of NF-kappaB. Acetylation of p65 both prolonged and increased IL10 transcription to enhance anti-inflammatory cytokine responses. We demonstrated that different pathogens such as Mycobacterium tuberculosis, M. leprae, Candida albicans, measles virus, and human immunodeficiency virus-1 interacted with DC-SIGN to activate the Raf-1-acetylation-dependent signaling pathway to modulate signaling by different TLRs. Thus, this pathway is involved in regulation of adaptive immunity by DCs to bacterial, fungal, and viral pathogens.

Original languageEnglish
Pages (from-to)605-16
Number of pages12
JournalImmunity
Volume26
Issue number5
DOIs
Publication statusPublished - May 2007

Cite this

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title = "C-type lectin DC-SIGN modulates Toll-like receptor signaling via Raf-1 kinase-dependent acetylation of transcription factor NF-kappaB",
abstract = "Adaptive immune responses by dendritic cells (DCs) are critically controlled by Toll-like receptor (TLR) function. Little is known about modulation of TLR-specific signaling by other pathogen receptors. Here, we have identified a molecular signaling pathway induced by the C-type lectin DC-SIGN that modulates TLR signaling at the level of the transcription factor NF-kappaB. We demonstrated that pathogens trigger DC-SIGN on human DCs to activate the serine and threonine kinase Raf-1, which subsequently leads to acetylation of the NF-kappaB subunit p65, but only after TLR-induced activation of NF-kappaB. Acetylation of p65 both prolonged and increased IL10 transcription to enhance anti-inflammatory cytokine responses. We demonstrated that different pathogens such as Mycobacterium tuberculosis, M. leprae, Candida albicans, measles virus, and human immunodeficiency virus-1 interacted with DC-SIGN to activate the Raf-1-acetylation-dependent signaling pathway to modulate signaling by different TLRs. Thus, this pathway is involved in regulation of adaptive immunity by DCs to bacterial, fungal, and viral pathogens.",
keywords = "Acetylation, Amino Acid Motifs, Cell Adhesion Molecules/genetics, Cells, Cultured, DNA/metabolism, Enzyme Activation, Humans, Interleukin-10/biosynthesis, Lectins, C-Type/genetics, NF-kappa B/metabolism, Phosphoserine/metabolism, Protein Binding, Protein-Serine-Threonine Kinases/metabolism, Proto-Oncogene Proteins c-raf/metabolism, Receptors, Antigen, T-Cell/metabolism, Receptors, Cell Surface/genetics, Signal Transduction, Toll-Like Receptor 3/metabolism, Toll-Like Receptor 4/metabolism, Toll-Like Receptor 5/metabolism, Toll-Like Receptors/metabolism, Transcription, Genetic/genetics, ras Proteins/metabolism",
author = "Gringhuis, {Sonja I} and {den Dunnen}, Jeroen and Manja Litjens and {van Het Hof}, Bert and {van Kooyk}, Yvette and Geijtenbeek, {Teunis B H}",
year = "2007",
month = "5",
doi = "10.1016/j.immuni.2007.03.012",
language = "English",
volume = "26",
pages = "605--16",
journal = "Immunity",
issn = "1074-7613",
publisher = "Cell Press",
number = "5",

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C-type lectin DC-SIGN modulates Toll-like receptor signaling via Raf-1 kinase-dependent acetylation of transcription factor NF-kappaB. / Gringhuis, Sonja I; den Dunnen, Jeroen; Litjens, Manja; van Het Hof, Bert; van Kooyk, Yvette; Geijtenbeek, Teunis B H.

In: Immunity, Vol. 26, No. 5, 05.2007, p. 605-16.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - C-type lectin DC-SIGN modulates Toll-like receptor signaling via Raf-1 kinase-dependent acetylation of transcription factor NF-kappaB

AU - Gringhuis, Sonja I

AU - den Dunnen, Jeroen

AU - Litjens, Manja

AU - van Het Hof, Bert

AU - van Kooyk, Yvette

AU - Geijtenbeek, Teunis B H

PY - 2007/5

Y1 - 2007/5

N2 - Adaptive immune responses by dendritic cells (DCs) are critically controlled by Toll-like receptor (TLR) function. Little is known about modulation of TLR-specific signaling by other pathogen receptors. Here, we have identified a molecular signaling pathway induced by the C-type lectin DC-SIGN that modulates TLR signaling at the level of the transcription factor NF-kappaB. We demonstrated that pathogens trigger DC-SIGN on human DCs to activate the serine and threonine kinase Raf-1, which subsequently leads to acetylation of the NF-kappaB subunit p65, but only after TLR-induced activation of NF-kappaB. Acetylation of p65 both prolonged and increased IL10 transcription to enhance anti-inflammatory cytokine responses. We demonstrated that different pathogens such as Mycobacterium tuberculosis, M. leprae, Candida albicans, measles virus, and human immunodeficiency virus-1 interacted with DC-SIGN to activate the Raf-1-acetylation-dependent signaling pathway to modulate signaling by different TLRs. Thus, this pathway is involved in regulation of adaptive immunity by DCs to bacterial, fungal, and viral pathogens.

AB - Adaptive immune responses by dendritic cells (DCs) are critically controlled by Toll-like receptor (TLR) function. Little is known about modulation of TLR-specific signaling by other pathogen receptors. Here, we have identified a molecular signaling pathway induced by the C-type lectin DC-SIGN that modulates TLR signaling at the level of the transcription factor NF-kappaB. We demonstrated that pathogens trigger DC-SIGN on human DCs to activate the serine and threonine kinase Raf-1, which subsequently leads to acetylation of the NF-kappaB subunit p65, but only after TLR-induced activation of NF-kappaB. Acetylation of p65 both prolonged and increased IL10 transcription to enhance anti-inflammatory cytokine responses. We demonstrated that different pathogens such as Mycobacterium tuberculosis, M. leprae, Candida albicans, measles virus, and human immunodeficiency virus-1 interacted with DC-SIGN to activate the Raf-1-acetylation-dependent signaling pathway to modulate signaling by different TLRs. Thus, this pathway is involved in regulation of adaptive immunity by DCs to bacterial, fungal, and viral pathogens.

KW - Acetylation

KW - Amino Acid Motifs

KW - Cell Adhesion Molecules/genetics

KW - Cells, Cultured

KW - DNA/metabolism

KW - Enzyme Activation

KW - Humans

KW - Interleukin-10/biosynthesis

KW - Lectins, C-Type/genetics

KW - NF-kappa B/metabolism

KW - Phosphoserine/metabolism

KW - Protein Binding

KW - Protein-Serine-Threonine Kinases/metabolism

KW - Proto-Oncogene Proteins c-raf/metabolism

KW - Receptors, Antigen, T-Cell/metabolism

KW - Receptors, Cell Surface/genetics

KW - Signal Transduction

KW - Toll-Like Receptor 3/metabolism

KW - Toll-Like Receptor 4/metabolism

KW - Toll-Like Receptor 5/metabolism

KW - Toll-Like Receptors/metabolism

KW - Transcription, Genetic/genetics

KW - ras Proteins/metabolism

U2 - 10.1016/j.immuni.2007.03.012

DO - 10.1016/j.immuni.2007.03.012

M3 - Article

VL - 26

SP - 605

EP - 616

JO - Immunity

JF - Immunity

SN - 1074-7613

IS - 5

ER -