Pathogen or Damage-activated C-Type Lectin Receptor Signaling Pathways

Click on one of the C-type Lectin receptors below to see the pathogen- or damage-associated molecules recognized by each receptor & the intracellular signaling pathways that are activated as a result.

DC-SIGN
DC-SIGN
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LSP1
LSP1
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KSR
KSR
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CNK
CNK
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Ras
Ras
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Raf-1
Raf-1
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MEK
MEK
TNF, IL-6
mRNA Decay
TNF, IL-6
mRNA Decay
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LARG
LARG
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RhoA
RhoA
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Ras
Ras
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Raf-1
Raf-1
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NF-kappa B p65
NF-kappa B p65
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RelB
RelB
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Inactive
Inactive
NF-kappa B p65
NF-kappa B p65
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NF-kappa B p50
NF-kappa B p50
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CBP
CBP
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p300
p300
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Pro-inflammatory Cytokines
Pro-inflammatory Cytokines
Dectin-1
Dectin-1
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SYK
SYK
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Src
Src
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NIK
NIK
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IKK alpha
IKK alpha
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NF-kappa B p100
NF-kappa B p100
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RelB
RelB
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NF-kappa B p52
NF-kappa B p52
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RelB
RelB
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NF-kappa B p52
NF-kappa B p52
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RelB
RelB
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ROS
ROS
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Mincle
Mincle
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FcR gamma
FcR gamma
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ROS
ROS
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SYK
SYK
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Dectin-2
Dectin-2
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FcR gamma
FcR gamma
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SYK
SYK
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Src
Src
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ROS
ROS
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PLC-gamma 2
PLC-gamma 2
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PIP2
PIP2
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DAG
DAG
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IP3
IP3
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PKC delta
PKC delta
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Bcl-10
Bcl-10
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CARD9
CARD9
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MALT1
MALT1
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IKK
IKK
I kappa B
I kappa B
I kappa B
I kappa B
Proteasome
Proteasome
NF-kappa B
NF-kappa B
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NF-kappa B p50
NF-kappa B p50
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Rel
Rel
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p38
p38
JNK
JNK
ERK1/2
ERK1/2
AP-1
AP-1
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IP3
IP3
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IP3 Receptor
IP3 Receptor
Calmodulin
Calmodulin
Calcineurin
Phosphatase
Calcineurin
Phosphatase
NFATC
NFATC
NFATC
NFATC
BDCA-2
BDCA-2
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FcR gamma
FcR gamma
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SYK
SYK
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BLNK
BLNK
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PLC-gamma 2
PLC-gamma 2
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BTK
BTK
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Calmodulin
Calmodulin
Calcineurin
Phosphatase
Calcineurin
Phosphatase
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MyD88
MyD88
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TLR9
TLR9
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Endosome
Endosome
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DCIR
DCIR
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SHP-1 or
SHP-2
SHP-1 or
SHP-2
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DCIR
DCIR
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SHP-1 or
SHP-2
SHP-1 or
SHP-2
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TLR8
TLR8
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MyD88
MyD88
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MICL/CLEC12A
MICL/CLEC12A
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SHP-1 or
SHP-2
SHP-1 or
SHP-2
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ERK
ERK
TLR Signaling
TLR Signaling
BDCA-2/CLEC4C
Select Ligand(s)
Mannose, fucose
Source(s)
Unknown
DCIR/CLEC4A
Select Ligand(s)
Mannose, fucose
Source(s)
HIV
DC-SIGN/CD209
Select Ligand(s)
High mannose, fucose, and Salp15, a protein produced by the salivary glands of Ixodes scapularis ticks that promotes the pathogenesis of Lyme disease
Source(s)
Candida albicans, cytomegalovirus, dengue virus, filoviruses, HIV, Leishmania spp., measles virus, Mycobacterium spp., SARS, Lewis antigens in Helicobacter pylori and Schistosoma mansoni
Dectin-1/CLEC7A
Select Ligand(s)
beta-1,3-linked glucans
Source(s)
Mycobacteria and fungi including Candida spp., Aspergillus spp., Coccidioides spp., and Pneumocystis spp.
Dectin-2/CLEC6A
Select Ligand(s)
High mannose, alpha-mannans
Source(s)
Mycobacterium tuberculosis, Schistosoma mansoni, house dust mite allergens, and fungi including Candida albicans, Cryptococcus neoformans, Histoplasma capsulatum, Microsporum audouinii, Paracoccidioides brasiliensis, Saccharomyces cerevisiae, Trichophyton rubrum
Mincle/CLEC4E
Select Ligand(s)
alpha-mannose, glycolipids including the mycobacterial cord factor trehalose 6,6'-dimycolate (TDM), and endogenous SAP130, a nuclear protein released by necrotic cells
Source(s)
Mycobacterium tuberculosis, dead cells, and fungi including Candida albicans, Malassezia spp., and Fonsecaea pedrosoi
MICL/CLEC12A
Select Ligand(s)
Unknown
Source(s)
Unknown

Overview of Pathogen- or Damage-activated C-type Lectin Receptor Signaling Pathways

C-type lectin receptors (CLRs) are a large family of soluble and transmembrane proteins that contain one or more distinct protein folds known as C-type lectin-like domains (CTLD). A small subset of these proteins has been categorized as pattern recognition receptors due to the fact that they are activated by specific pathogen- or damage-associated molecules and induce signaling pathways that regulate the immune response. With the exception of DC-SIGN, most CLRs that function in this way belong to either the Dectin-1 (Dectin-1, CLEC-1, CLEC-2, CLEC9a, CLEC12B, LOX-1/OLR1, and MICL/CLEC12A) or Dectin-2 (Dectin-2, BDCA-2, CLEC4D/CLECSF8, DCAR, DCIR, and Mincle) subfamilies. These receptors are type II transmembrane proteins that are highly expressed on monocytes, macrophages, and/or dendritic cells and are variably expressed by a number of other cell types. They recognize carbohydrates such as glucans, fucose, and high mannose structures present in mycobacteria, viruses, and fungi. In addition, some CLRs are activated by host-derived damage signals.

Dectin-1, Dectin-2, and Mincle are three well-characterized pathogen recognition CLRs that induce canonical NF-kappa B signaling, MAPK signaling, and NFAT-dependent transcription. Activation of these pathways occurs following phosphorylation of either the cytoplasmic hemi-immunoreceptor tyrosine-based activation motif (hemITAM) domain in Dectin-1 or the ITAM-containing FcR gamma adaptor protein that associates with Dectin-2 and Mincle. These phosphorylation events, mediated primarily by Src family kinases, create a docking site for spleen tyrosine kinase (SYK), which triggers SYK-mediated phagocytosis, the generation of reactive oxygen species (ROS), and activation of PLC-gamma 2. PLC-gamma 2 catalyzes the hydrolysis of phosphatidylinositol 4, 5-bisphosphate (PIP2), leading to an IP3-dependent Ca2+ flux and activation of PKC delta by diacylglycerol (DAG). Signaling through PKC delta stimulates a multiprotein complex consisting of CARD9, Bcl-10, and MALT1, which activates I kappa b kinase (IKK) and multiple mitogen-activated protein kinases (MAPKs) including p38, JNK, and ERK1/2. IKK subsequently phosphorylates I kappa B and promotes the nuclear translocation of NF-kappa B, while p38, JNK, and ERK1/2 phosphorylate and activate AP-1. In addition to activating the canonical NF-kappa B signaling pathway, Dectin-1 signaling also regulates NF-kappa B activity through the NIK-dependent, non-canonical NF-kappa B pathway and by Raf-1-mediated phosphorylation. Raf-1-induced phosphorylation of NF-kappa B leads to acetylation of its p65 subunit by CREB binding protein (CBP) and p300, which enhances its transcriptional activity. As a result of their abilities to regulate signaling pathways that promote the activities of NF-kappa B, AP-1, and C/EBP, Dectin-1, Dectin-2, and Mincle control the expression of a wide range of cytokines that direct the innate and adaptive immune response.

Similar to Dectin-1, DC-SIGN/CD209 signaling has been shown to activate Raf-1-mediated NF-kappa B phosphorylation, but how this receptor initiates intracellular signaling is not clear. Both Src family kinases and p21-activated kinases (PAKs) phosphorylate Raf-1 downstream of DC-SIGN/CD209, but the intracellular signaling molecules that sense DC-SIGN activation and promote Raf-1 phosphorylation by Src and PAKs are not known. DC-SIGN/CD209 signaling is further complicated by the observation that this receptor can activate different signaling pathways depending on the pathogen that it detects and this can alter the outcome of the immune response. Both DC-SIGN/CD209 and BDCA-2 modulate Toll-like receptor (TLR) signaling, although this seems to occur through two different pathways as BDCA-2 has not been shown to signal through Raf-1. Instead, BDCA-2 associates with FcR gamma and recruits SYK, which then signals through a complex consisting of PLC-gamma 2, B cell linker (BLNK), and Bruton’s tyrosine kinase (BTK) to promote Ca2+ mobilization. Mobilization of Ca2+ may negatively regulate TLR signaling through activation of Calcineurin phosphatase, which inhibits the TLR adaptor protein MyD88.

In contrast to the ITAM-containing receptors, DCIR/CLEC4A, MICL/CLEC12A, and CLEC12B contain an immunoreceptor tyrosine-based inhibitory motif (ITIM) in their cytoplasmic domains. Following activation, this domain in DCIR/CLEC4A or MICL/CLEC12A recruits the SHP-1 or SHP-2 phosphatases and inhibits TLR8 or TLR9 signaling through an undefined mechanism. Less is known about the ligand specificity and downstream signaling pathways activated by other members of the Dectin-1 and Dectin-2 subfamilies. Since these receptors are important for both anti-fungal immunity and for the recognition of endogenous ligands, further investigation of the signaling pathways and the biological effects that they promote is necessary.

To learn more, please visit our C-type Lectin Receptors Research Area.

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