CLEC5A

Last updated
CLEC5A
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases CLEC5A , CLECSF5, MDL-1, MDL1, C-type lectin domain family 5 member A, C-type lectin domain containing 5A
External IDs OMIM: 604987 MGI: 1345151 HomoloGene: 8302 GeneCards: CLEC5A
Orthologs
SpeciesHumanMouse
Entrez

23601

23845

Ensembl

ENSG00000258227

ENSMUSG00000029915

UniProt

Q9NY25

Q9R007

RefSeq (mRNA)

NM_001301167
NM_013252

NM_001038604
NM_021364

RefSeq (protein)

NP_001288096
NP_037384

NP_001033693
NP_067339

Location (UCSC) Chr 7: 141.93 – 141.95 Mb Chr 6: 40.55 – 40.56 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

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 that in humans is encoded by the CLEC5A gene. [5] [6]

Contents

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 to generate signals via Syk pathway. [7]

MDL-1 is highly expressed on myeloid lineages like neutrophil, monocyte, macrophage and also osteoclast, microglia and dendritic cells. [8]

Activation of MDL-1 induces production of many cytokines (TNF-α, IL-1, IL-6, IL-8 and IL-17A) and chemokines (MIP-1α, RANTES, IP-10, MDC). MDL-1 also amplifies innate immune response. [7]

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. [8]

Another pathogen is influenza virus and its hemagglutinin protein, which interacts with CLEC5A. Through this interaction is stimulated innate immune response and it leads to secretion of proinflammatory cytokines. [9]

The researchers discovered that Japanese encephalitis virus (JEV) also binds to CLEC5A and contributes to viral pathology. [8]

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. Blockade of CLEC5A signaling in DV infected cells can attenuate vascular leakage and increase survival of patients with DHF and DSS. [8]

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. [9]

For the Japanese encephalitis virus, blockade of CLEC5A cannot inhibit infection of neurons and astrocytes, however anti-CLEC5A decreases proinflammatory cytokines and toxic substances released from microglia. [8]

Related Research Articles

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 the innate immune system, such as dendritic cells, macrophages, monocytes, neutrophils and epithelial cells, to identify two classes of molecules: pathogen-associated molecular patterns (PAMPs), which are associated with microbial pathogens, and damage-associated molecular patterns (DAMPs), which are associated with components of host's cells that are released during cell damage or death. They are also called primitive pattern recognition receptors because they evolved before other parts of the immune system, particularly before adaptive immunity. PRRs also mediate the initiation of antigen-specific adaptive immune response and release of inflammatory cytokines.

<span class="mw-page-title-main">Interleukin 3</span>

Interleukin 3 (IL-3) is a protein that in humans is encoded by the IL3 gene localized on chromosome 5q31.1. Sometimes also called colony-stimulating factor, multi-CSF, mast cell growth factor, MULTI-CSF, MCGF; MGC79398, MGC79399: the protein contains 152 amino acids and its molecular weight is 17 kDa. IL-3 is produced as a monomer by activated T cells, monocytes/macrophages and stroma cells. The major function of IL-3 cytokine is to regulate the concentrations of various blood-cell types. It induces proliferation and differentiation in both early pluripotent stem cells and committed progenitors. It also has many more specific effects like the regeneration of platelets and potentially aids in early antibody isotype switching.

<span class="mw-page-title-main">DC-SIGN</span> Protein-coding gene in the species Homo sapiens

DC-SIGN also known as CD209 is a protein which in humans is encoded by the CD209 gene.

<span class="mw-page-title-main">Tyrosine-protein kinase SYK</span>

Tyrosine-protein kinase SYK, also known as spleen tyrosine kinase, is an enzyme which in humans is encoded by the SYK gene.

NKG2 also known as CD159 is a receptor for natural killer cells. There are 7 NKG2 types: A, B, C, D, E, F and H. NKG2D is an activating receptor on the NK cell surface. NKG2A dimerizes with CD94 to make an inhibitory receptor (CD94/NKG2).

<span class="mw-page-title-main">STAT2</span> Protein-coding gene in Homo sapiens

Signal transducer and activator of transcription 2 is a protein that in humans is encoded by the STAT2 gene. It is a member of the STAT protein family. This protein is critical to the biological response of type I interferons (IFNs). STAT2 sequence identity between mouse and human is only 68%.

<span class="mw-page-title-main">TYROBP</span> Protein-coding gene in the species Homo sapiens

TYRO protein tyrosine kinase-binding protein is an adapter protein that in humans is encoded by the TYROBP gene.

<span class="mw-page-title-main">CLEC4M</span> Protein-coding gene in the species Homo sapiens

C-type lectin domain family 4 member M is a protein that in humans is encoded by the CLEC4M gene. CLEC4M has also been designated as CD299.

<span class="mw-page-title-main">CD93</span>

CD93 is a protein that in humans is encoded by the CD93 gene. CD93 is a C-type lectin transmembrane receptor which plays a role not only in cell–cell adhesion processes but also in host defense.

<span class="mw-page-title-main">CLEC7A</span> Protein-coding gene in the species Homo sapiens

C-type lectin domain family 7 member A or Dectin-1 is a protein that in humans is encoded by the CLEC7A gene. CLEC7A is a member of the C-type lectin/C-type lectin-like domain (CTL/CTLD) superfamily. The encoded glycoprotein is a small type II membrane receptor with an extracellular C-type lectin-like domain fold and a cytoplasmic domain with a partial immunoreceptor tyrosine-based activation motif. It functions as a pattern-recognition receptor for a variety of β-1,3-linked and β-1,6-linked glucans from fungi and plants, and in this way plays a role in innate immune response. Expression is found on myeloid dendritic cells, monocytes, macrophages and B cells. Alternate transcriptional splice variants, encoding different isoforms, have been characterized. This gene is closely linked to other CTL/CTLD superfamily members on chromosome 12p13 in the natural killer gene complex region.

<span class="mw-page-title-main">TREM1</span> Protein-coding gene in the species Homo sapiens

Triggering receptor expressed on myeloid cells 1 (TREM1) an immunoglobulin (Ig) superfamily transmembrane protein that, in humans, is encoded by the TREM1 gene. TREM1 is constitutively expressed on the surface of peripheral blood monocytes and neutrophils, and upregulated by toll-like receptor (TLR) ligands; activation of TREM1 amplifies immune responses.

<span class="mw-page-title-main">CLEC1B</span>

C-type lectin domain family 1 member B is a protein that in humans is encoded by the CLEC1B gene.

<span class="mw-page-title-main">TREM2</span> Protein-coding gene in the species Homo sapiens

Triggering receptor expressed on myeloid cells 2(TREM2) is a protein that in humans is encoded by the TREM2 gene. TREM2 is expressed on macrophages, immature monocyte-derived dendritic cells, osteoclasts, and microglia, which are immune cells in the central nervous system. In the liver, TREM2 is expressed by several cell types, including macrophages, that respond to injury. In the intestine, TREM2 is expressed by myeloid-derived dendritic cells and macrophage. TREM2 is overexpressed in many tumor types and has anti-inflammatory activities. It might therefore be a good therapeutic target.

<span class="mw-page-title-main">CLEC4A</span>

C-type lectin domain family 4 member A is a protein that in humans is encoded by the CLEC4A gene.

<span class="mw-page-title-main">CLEC2B</span>

C-type lectin domain family 2 member B is a protein that in humans is encoded by the CLEC2B gene.

<span class="mw-page-title-main">CLEC12A</span> Protein-coding gene in humans

C-type lectin domain family 12 member A is a protein that in humans is encoded by the CLEC12A gene.

<span class="mw-page-title-main">CLEC10A</span> Protein-coding gene in the species Homo sapiens

C-type lectin domain family 10 member A also known as CLEC10A is a protein that in humans is encoded by the CLEC10A gene.

<span class="mw-page-title-main">NKG2D</span> Protein-coding gene in the species Homo sapiens

NKG2D is an activating receptor (transmembrane protein) belonging to the NKG2 family of C-type lectin-like receptors. NKG2D is encoded by KLRK1 (killer cell lectin like receptor K1) gene which is located in the NK-gene complex (NKC) situated on chromosome 6 in mice and chromosome 12 in humans. In mice, it is expressed by NK cells, NK1.1+ T cells, γδ T cells, activated CD8+ αβ T cells and activated macrophages. In humans, it is expressed by NK cells, γδ T cells and CD8+ αβ T cells. NKG2D recognizes induced-self proteins from MIC and RAET1/ULBP families which appear on the surface of stressed, malignant transformed, and infected cells.

<span class="mw-page-title-main">CLEC9A</span>

C-type lectin domain family 9 member A is a protein that in humans is encoded by the CLEC9A gene.

<span class="mw-page-title-main">CLEC6A</span>

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/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 recognizing α-mannans and as such plays an important role in innate immune response to fungi. Expression is found on macrophages and dendritic cells. It can also be found at low levels in Langerhans cells and peripheral blood monocytes, where expression levels could be increased upon induction of inflammation.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000258227 - Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000029915 - Ensembl, May 2017
  3. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ↑ "Entrez Gene: C-type lectin domain family 5".
  6. ↑ Bakker AB, Baker E, Sutherland GR, Phillips JH, Lanier LL (August 1999). "Myeloid DAP12-associating lectin (MDL)-1 is a cell surface receptor involved in the activation of myeloid cells". Proceedings of the National Academy of Sciences of the United States of America. 96 (17): 9792–6. Bibcode:1999PNAS...96.9792B. doi: 10.1073/pnas.96.17.9792 . PMC   22289 . PMID   10449773.
  7. 1 2 Cheung R, Shen F, Phillips JH, McGeachy MJ, Cua DJ, Heyworth PG, Pierce RH (November 2011). "Activation of MDL-1 (CLEC5A) on immature myeloid cells triggers lethal shock in mice". The Journal of Clinical Investigation. 121 (11): 4446–61. doi:10.1172/jci57682. PMC   3204838 . PMID   22005300.
  8. 1 2 3 4 5 Sung PS, Hsieh SL (2019-12-06). "CLEC2 and CLEC5A: Pathogenic Host Factors in Acute Viral Infections". Frontiers in Immunology. 10: 2867. doi: 10.3389/fimmu.2019.02867 . PMC   6909378 . PMID   31867016.
  9. 1 2 Teng O, Chen ST, Hsu TL, Sia SF, Cole S, Valkenburg SA, et al. (January 2017). "CLEC5A-Mediated Enhancement of the Inflammatory Response in Myeloid Cells Contributes to Influenza Virus Pathogenicity In Vivo". Journal of Virology. 91 (1). doi:10.1128/jvi.01813-16. PMC   5165214 . PMID   27795434.

Further reading

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