C-type lectin domain family 5 member A (CLEC5A), also known as C-type lectin superfamily member 5 (CLECSF5) and myeloid DAP12-associating lectin 1 (MDL-1) is a
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 ...
that in humans is encoded by the ''CLEC5A''
gene
In biology, the word gene (from , ; "... Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a b ...
.
Structurally MDL-1 is a type II transmembrane protein with a short cytoplasmic tail and without signaling motifs, therefore it requires association with the adaptor protein
DAP12
TYRO protein tyrosine kinase-binding protein is an adapter protein that in humans is encoded by the ''TYROBP'' gene.
Function
This gene encodes a transmembrane signaling polypeptide which contains an immunoreceptor tyrosine-based activation mo ...
to generate signals via
Syk pathway.
MDL-1 is highly expressed on myeloid lineages like
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 ...
,
monocyte
Monocytes are a type of leukocyte or white blood cell. They are the largest type of leukocyte in blood and can differentiate into macrophages and conventional dendritic cells. As a part of the vertebrate innate immune system monocytes also ...
,
macrophage and also
osteoclast
An osteoclast () is a type of bone cell that breaks down bone tissue. This function is critical in the maintenance, repair, and remodeling of bones of the vertebral skeleton. The osteoclast disassembles and digests the composite of hydrated pro ...
,
microglia and
dendritic cells
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. The ...
.
Activation of MDL-1 induces production of many cytokines (
TNF-α
Tumor necrosis factor (TNF, cachexin, or cachectin; formerly known as tumor necrosis factor alpha or TNF-α) is an adipokine and a cytokine. TNF is a member of the TNF superfamily, which consists of various transmembrane proteins with a homolog ...
,
IL-1,
IL-6,
IL-8 and
IL-17A) and chemokines (
MIP-1α,
RANTES
Chemokine (C-C motif) ligand 5 (also CCL5) is a protein which in humans is encoded by the ''CCL5'' gene. The gene has been discovered in 1990 by ''in situ'' hybridisation and it is localised on 17q11.2-q12 chromosome. It is also known as RANTES ...
,
IP-10, MDC). MDL-1 also amplifies innate immune response.
Viral pathology
The most known ligand for CLEC5A is
dengue virus (DV). Activated CLEC5A by binding to the dengue virion leads to phosphorylation of DAP12 and through Syk pathway are induced proinflammatory cytokines. CLEC5A is responsible for dengue virus induced hemorrhagic fever (
DHF) and dengue shock syndrome (DSS), which is the most severe immune response to dengue virus infection and it is characterized by plasma leakage because of the increased vascular permeability. Interaction of CLEC5A and dengue virus also induces osteolytic activity.
Another pathogen is influenza virus and its
hemagglutinin
In molecular biology, hemagglutinins (or ''haemagglutinin'' in British English) (from the Greek , 'blood' + Latin , 'glue') are receptor-binding membrane fusion glycoproteins produced by viruses in the '' Paramyxoviridae'' family. Hemagglutinins a ...
protein, which interacts with CLEC5A. Through this interaction is stimulated innate immune response and it leads to secretion of proinflammatory cytokines.
The researchers discovered that Japanese encephalitis virus (JEV) also binds to CLEC5A and contributes to viral pathology.
Use in therapy
With the discovery of CLEC5A interactions with different viruses, scientists are testing blocking anti-CLEC5A antibodies, Syk pathway inhibitors and CLEC5A deficient mice to discover CLEC5A contribution to pathological progress.
In the case of dengue virus, monoclonal anti-CLEC5A antibodies are able to suppress the secretion of proinflammatory cytokines without affecting
IFN-α
The type-I interferons (IFN) are cytokines which play essential roles in inflammation, immunoregulation, tumor cells recognition, and T-cell responses. In the human genome, a cluster of thirteen functional IFN genes is located at the 9p21.3 cyt ...
. Blockade of CLEC5A signaling in DV infected cells can attenuate vascular leakage and increase survival of patients with DHF and DSS.
In lethal challenges of recombinant
H5N1 influenza virus, the CLEC5A deficient mice showed reduced levels of proinflammatory cytokines, decreased immune cell infiltration in the lungs and improved survival compared to the wild-type mice even with comparable viral loads.
For the Japanese encephalitis virus, blockade of CLEC5A cannot inhibit infection of
neurons and
astrocytes
Astrocytes (from Ancient Greek , , "star" + , , "cavity", "cell"), also known collectively as astroglia, are characteristic star-shaped glial cells in the brain and spinal cord. They perform many functions, including biochemical control of endo ...
, however anti-CLEC5A decreases proinflammatory cytokines and toxic substances released from microglia.
References
Further reading
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External links
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C-type lectins
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