Dectin-2 or C-type lectin domain containing 6A is a protein that in humans is encoded by the CLEC6A gene.
Dectin-2 is a member of the
C-type lectin
A C-type lectin (CLEC) is a type of carbohydrate-binding protein known as a lectin. The C-type designation is from their requirement for calcium for binding. Proteins that contain C-type lectin domains have a diverse range of functions including ...
/C-type lectin-like domain (CTL/CTLD) superfamily. The encoded protein is a type II transmembrane protein with an extracellular carbohydrate recognition domain. It functions as a
pattern recognition receptor
Pattern recognition receptors (PRRs) play a crucial role in the proper function of the innate immune system. PRRs are germline-encoded host sensors, which detect molecules typical for the pathogens. They are proteins expressed, mainly, by cells of ...
recognizing α-mannans and as such plays an important role in
innate immune response
The innate, or nonspecific, immune system is one of the two main immunity strategies (the other being the adaptive immune system) in vertebrates. The innate immune system is an older evolutionary defense strategy, relatively speaking, and is the ...
to fungi. Expression is found on
macrophage
Macrophages (abbreviated as M φ, MΦ or MP) ( el, large eaters, from Greek ''μακρός'' (') = large, ''φαγεῖν'' (') = to eat) are a type of white blood cell of the immune system that engulfs and digests pathogens, such as cancer cel ...
s and
dendritic cell
Dendritic cells (DCs) are antigen-presenting cells (also known as ''accessory cells'') of the mammalian immune system. Their main function is to process antigen material and present it on the cell surface to the T cells of the immune system. ...
s. It can also be found at low levels in
Langerhans cell
A Langerhans cell (LC) is a tissue-resident macrophage of the skin. These cells contain organelles called Birbeck granules. They are present in all layers of the epidermis and are most prominent in the stratum spinosum. They also occur in the ...
s and peripheral blood monocytes, where expression levels could be increased upon induction of inflammation.
Dectin-2 genes are located in the telomeric region of the natural killer gene cluster on mouse chromosome 6 and human chromosome 12. The dectin-2 cluster is composed of genes encoding dectin-2, DCIR, DCAR, BDCA-2, Mincle and Clecsf8, which are the members of the group II C-type lectin family.
Structure
Dectin-2 is a glycosylated type II transmembrane protein which is encoded by six exons. It consists of a single C-type lectin (carbohydrate recognition domain, CRD) domain in its extracellular region, a stalk region, a transmembrane region and a cytoplasmic domain. Its CRD domain contains a glutamic acid-proline-asparagine (EPN) motif, which is Ca
2+ dependent.
The cytoplasmic domain is generally short. Unlike
dectin-1, it has no known signaling motif in its cytoplasmic region. Instead, upon ligand binding, dectin-2 transduces signal via association with the ITAM-containing
Fc receptor γ chain.
Signaling
Dectin-2 is a member of C-type lectin receptor family, which is a group of pattern recognition receptors involved in antifungal immunity, homeostasis and induction of immune response to pathogens. Its carbohydrate recognition domain is capable of binding α-mannans in fungal cell walls. Upon ligand binding, dectin-2 transduces the signal via an ITAM-bearing adaptor protein FcγR. This results in recruitment of
Syk
Tyrosine-protein kinase SYK, also known as spleen tyrosine kinase, is an enzyme which in humans is encoded by the ''SYK'' gene.
Function
SYK, along with ZAP70, is a member of the Syk family of tyrosine kinases. These cytoplasmic non-receptor t ...
and downstream activation of so-called CBM (
CARD9
Caspase recruitment domain-containing protein 9 is an adaptor protein of the CARD-CC protein family, which in humans is encoded by the ''CARD9'' gene. It mediates signals from pattern recognition receptors to activate pro-inflammatory and anti-i ...
-
BCL10
B-cell lymphoma/leukemia 10 is a protein that in humans is encoded by the ''BCL10'' gene. Like BCL2, BCL3, BCL5, BCL6, BCL7A, and BCL9, it has clinical significance in lymphoma.
Function
Bcl10 was identified by its translocation in a case of ...
-
MALT1
Mucosa-associated lymphoid tissue lymphoma translocation protein 1 is a protein that in humans is encoded by the ''MALT1'' gene. It's the human paracaspase.
Function
Genetic ablation of the paracaspase gene in mice and biochemical studies have ...
) signalling complex, leading to
NFκB activation and resulting in production of cytokines, including
IL-6,
IL-23 and
IL-1β
Interleukin-1 beta (IL-1β) also known as leukocytic pyrogen, leukocytic endogenous mediator, mononuclear cell factor, lymphocyte activating factor and other names, is a cytokine protein that in humans is encoded by the ''IL1B'' gene."Catabolin" ...
.
Aforementioned signaling pathway leads to induction of
phagocytosis
Phagocytosis () is the process by which a cell uses its plasma membrane to engulf a large particle (≥ 0.5 μm), giving rise to an internal compartment called the phagosome. It is one type of endocytosis. A cell that performs phagocytosis is ...
and production of inflammatory mediators, such as
cytokine
Cytokines are a broad and loose category of small proteins (~5–25 kDa) important in cell signaling. Cytokines are peptides and cannot cross the lipid bilayer of cells to enter the cytoplasm. Cytokines have been shown to be involved in autocrin ...
s and
chemokine
Chemokines (), or chemotactic cytokines, are a family of small cytokines or signaling proteins secreted by cells that induce directional movement of leukocytes, as well as other cell types, including endothelial and epithelial cells. In additio ...
s, induction of both innate and adaptive immunity and overall antimicrobial response.
Signaling induced by dectin-2 activation also augments
IL-17RC expression in
neutrophil
Neutrophils (also known as neutrocytes or heterophils) are the most abundant type of granulocytes and make up 40% to 70% of all white blood cells in humans. They form an essential part of the innate immune system, with their functions varying in ...
s, and is involved in
IL-17A and IL-17RC autocrine feedback loop, which is important for ROS production and subsequent elimination of fungal pathogen.
Dectin-2 has also been reported to be involved in activation of MAPK signaling.
E3 ubiqitin ligase CBLB has been described as negative regulator of dectin-2.
Ligands
Dectin-2 is known to recognize α-mannans, which are an important component of fungal cell wall. It has also been reported to recognize glycoproteins rich in O-mannobiose residues.
Functions
Anti-fungal immunity
Dectin-2 signaling is an essential component of host defense against fungal infections. It has been observed that dectin-2 preferentially induces the
Th17 response, which is essential for effective host protection and elimination of fungal pathogens. Cytokines produced after dectin-2 activation include IL-6, IL-23 and IL-1β, all of which are typical for Th17 response. Dectin-2 can also induce production of
IL-12, which stimulates
Th1 lymphocytes to produce
IFN-γ
Interferon gamma (IFN-γ) is a dimerized soluble cytokine that is the only member of the type II class of interferons. The existence of this interferon, which early in its history was known as immune interferon, was described by E. F. Wheelock ...
. This in turn leads to activation of macrophages and contributes to fungal eradication.
Anti-inflammatory cytokines such as IL-2 and IL-10 can also be induced by dectin-2.
Most abundantly studied is the role of dectin-2 in ''
Candida albicans
''Candida albicans'' is an opportunistic pathogenic yeast that is a common member of the human gut flora. It can also survive outside the human body. It is detected in the gastrointestinal tract and mouth in 40–60% of healthy adults. It is us ...
'' infections, and it has been observed that this receptor is important for effective host defense and ''C. albicans'' clearance. Mice lacking dectin-2 demonstrated greatly increased susceptibility to ''C. albicans'' infections, supporting that this receptor is essential for the induction of effective immune response. The functions of dectin-2 appear to differ between the yeast and hyphal forms of ''C. albicans''. Possibly due to different cell wall ligands, as these two forms are known to slightly differ in terms of cell wall organization. Dectin-2 could possibly be able to distinguish between the two morphological forms of ''C. albicans''.
Dectin-2 has also been shown to interact with Dectin-3, witch which it can form a heterodimer in order to mediate the immune defense against ''Candida albicans''.
While Dectin-2 is known to mediate immune response to ''Candida albicans'', it recognizes a variety of different pathogens, which include ''
Candida glabrata
''Candida glabrata'' is a species of haploid yeast of the genus ''Candida'', previously known as ''Torulopsis glabrata''. Despite the fact that no sexual life cycle has been documented for this species, ''C. glabrata'' strains of both mating ty ...
'', ''
Cryptococcus neoformans
''Cryptococcus neoformans'' is an encapsulated yeast belonging to the class Tremellomycetes and an obligate aerobe that can live in both plants and animals. Its teleomorph is a filamentous fungus, formerly referred to ''Filobasidiella neoformans' ...
'', ''
Aspergillus fumigatus
''Aspergillus fumigatus'' is a species of fungus in the genus ''Aspergillus'', and is one of the most common ''Aspergillus'' species to cause disease in individuals with an immunodeficiency.
''Aspergillus fumigatus'', a saprotroph widespread in ...
'', ''
Saccharomyces cerevisiae
''Saccharomyces cerevisiae'' () (brewer's yeast or baker's yeast) is a species of yeast (single-celled fungus microorganisms). The species has been instrumental in winemaking, baking, and brewing since ancient times. It is believed to have been o ...
'', ''
Mycobacterium tuberculosis
''Mycobacterium tuberculosis'' (M. tb) is a species of pathogenic bacteria in the family Mycobacteriaceae and the causative agent of tuberculosis. First discovered in 1882 by Robert Koch, ''M. tuberculosis'' has an unusual, waxy coating on its c ...
'', ''
Paracoccidioides brasiliensis
''Paracoccidioides brasiliensis'' is a dimorphic fungus and one of the two species that cause paracoccidioidomycosis (the other being ''Paracoccidioides lutzii).'' The fungus has been affiliated with the family Ajellomycetaceae (division Ascomyco ...
'' and ''
Histoplasma capsulatum
''Histoplasma capsulatum'' is a species of dimorphic fungus. Its sexual form is called ''Ajellomyces capsulatus''. It can cause pulmonary and disseminated histoplasmosis.
''H. capsulatum'' is "distributed worldwide, except in Antarctica, but m ...
'' among other species.
Other functions
Dectin-2 has also been linked to allergic responses. It is reportedly able to recognize the
house dust mite
House dust mites (HDM, or simply dust mites) are various species of acariform mites belonging to the family Pyroglyphidae that are found in association with dust in dwellings. They are known for causing allergies.
Biology
Species
The current ...
(arachnids known to cause allergy), and subsequently induce cysteinyl leukotriene production. These mediators, along with cytokines such as
IL-33
Interleukin 33 (IL-33) is a protein that in humans is encoded by the ''IL33'' gene.
Interleukin 33 is a member of the IL-1 family that potently drives production of T helper-2 (Th2)-associated cytokines (e.g., IL-4). IL33 is a ligand for ST2 ...
, are essential for the initiation of airway inflammation and for induction of
Th2 response.
References
{{reflist
C-type lectins