CLEC4M - C-type lectin domain family 4 member M |Elisa - Clia - Antibody - Protein

Background

CLEC4M (C-type lectin domain family 4 member M), also known as L-SIGN (liver/lymph node-specific ICAM-3 grabbing non-integrin), is a member of the C-type lectin receptor family that primarily functions as a carbohydrate-binding receptor on endothelial cells. CLEC4M is highly expressed on sinusoidal endothelial cells, particularly in the liver and lymph nodes. This receptor is involved in pathogen recognition and immune response modulation, functioning in cellular adhesion and interactions with a variety of pathogens through specific carbohydrate binding. CLEC4M plays a role in the immune system’s surveillance of pathogens and in mediating interactions with viruses, bacteria, and other infectious agents, particularly in tissues involved in blood filtration and immune processing.

CLEC4M has garnered significant interest due to its ability to bind to glycosylated molecules on pathogens, such as viruses like SARS-CoV, HIV-1, and hepatitis C, contributing to viral capture and cellular entry. Additionally, it can act as a trans-infection receptor, where it captures viruses on non-permissive cells, which are then transferred to permissive cells to facilitate viral replication. Thus, CLEC4M’s role in pathogen recognition and immune response regulation is crucial to both its physiological function and its involvement in disease.

Protein Structure

The structure of CLEC4M is critical to its function as a pathogen recognition receptor, allowing it to bind to specific carbohydrates on the surfaces of foreign molecules:

C-Type Lectin Domain:

• The defining feature of CLEC4M is its C-type lectin domain (CTLD), which is responsible for carbohydrate recognition and binding. This domain binds to mannose and other carbohydrate residues, facilitating pathogen attachment to the receptor. The C-type lectin domain is calcium-dependent, which is essential for stabilizing the carbohydrate-binding pocket and increasing the affinity for pathogen-associated sugars.

Extracellular Region:

• CLEC4M has an extracellular region composed of a stalk region and the C-type lectin domain. The stalk region, which precedes the lectin domain, is flexible and extends the CTLD away from the cell membrane, enhancing accessibility to pathogens. This stalk region may contain repeated sequences that enable multimerization, allowing CLEC4M to form tetramers or other oligomeric structures, which increase its avidity for ligands on pathogen surfaces.

Transmembrane Domain:

• The transmembrane domain anchors CLEC4M within the cell membrane of endothelial cells. This domain plays a role in cellular localization and stability but does not directly participate in ligand binding. However, it anchors the extracellular components firmly within the lipid bilayer, which is necessary for CLEC4M’s functional positioning on the cell surface.

Cytoplasmic Tail:

• CLEC4M’s cytoplasmic tail is relatively short and lacks known signaling motifs, indicating that it may primarily function in ligand binding and pathogen capture rather than initiating intracellular signaling. However, this tail may interact with other cellular components to stabilize CLEC4M’s surface expression or mediate endocytosis upon ligand binding.

Classification and Subtypes

CLEC4M belongs to the C-type lectin receptor (CLR) family, which includes several receptors involved in carbohydrate recognition. Within this family, CLEC4M is closely related to DC-SIGN (Dendritic Cell-Specific Intercellular adhesion molecule-3-Grabbing Non-integrin), another lectin receptor with a similar structure and function, particularly in pathogen binding. Despite their functional similarities, CLEC4M and DC-SIGN are differentially expressed, with CLEC4M predominantly expressed in liver sinusoidal and lymph node endothelial cells, whereas DC-SIGN is expressed in dendritic cells and macrophages. These variations in tissue distribution allow for tissue-specific immune responses to pathogens.

CLEC4M does not have subtypes but is part of a broader family of receptors that vary in their carbohydrate-binding affinities and expression patterns, adapting to diverse roles in pathogen surveillance and immune regulation.

Function and Biological Significance

CLEC4M serves essential functions in pathogen recognition and immune modulation:

Pathogen Recognition and Binding:

• CLEC4M’s primary role involves recognizing and binding to carbohydrate structures, specifically mannose-rich glycans, present on the surface of pathogens such as viruses, bacteria, and fungi. This binding is mediated by the C-type lectin domain, which interacts with glycosylated molecules on pathogens, capturing them at the cell surface.

Viral Capture and Trans-Infection:

• CLEC4M is known to facilitate viral entry and trans-infection by capturing viruses on non-permissive cells and transferring them to permissive cells, such as hepatocytes or lymphocytes, where viral replication can occur. For instance, CLEC4M has been shown to bind to the spike protein of SARS-CoV, facilitating the virus's capture and transfer within the liver and lymphoid tissues. This receptor also binds HIV-1, dengue virus, and other pathogens, highlighting its broad specificity and role in pathogen dissemination.

Modulation of Immune Responses:

• Beyond pathogen binding, CLEC4M is involved in modulating immune responses by facilitating interactions with various immune cells. For instance, it can bind to ICAM-3 on T cells, promoting cell adhesion and communication. This function supports the immune surveillance role of :
  endothelial cells in organs like the liver, where CLEC4M captures circulating antigens for immune processing.

Endocytosis and Antigen Presentation:

• Upon binding pathogens, CLEC4M can mediate endocytosis, allowing pathogens or antigens to be internalized and processed for antigen presentation. This pathway links CLEC4M to adaptive immunity by presenting pathogen-derived molecules to immune cells, thus contributing to the body’s ability to generate specific immune responses against the captured pathogens.

Clinical Issues

Viral Infections:

• CLEC4M’s interaction with viruses such as HIV-1, SARS-CoV, and hepatitis C virus has clinical significance. Through its role in capturing these viruses, CLEC4M may facilitate viral spread within the host, especially in tissues rich in CLEC4M-expressing cells, such as the liver and lymph nodes. In the context of HIV-1, CLEC4M’s ability to capture and transmit the virus to target immune cells has implications for viral persistence and immune evasion.

Role in Hepatitis C and Liver Disease:

• CLEC4M is implicated in liver disease due to its high expression in liver endothelial cells and its ability to interact with hepatitis C virus (HCV). By capturing HCV, CLEC4M may facilitate its transmission and chronic infection, contributing to liver inflammation and potentially progressing to fibrosis and cirrhosis. Targeting CLEC4M or its ligand interactions may offer therapeutic strategies to limit HCV transmission and liver disease progression.

Immune Evasion and Pathogen Persistence:

• Pathogens that utilize CLEC4M for binding and immune evasion can establish persistent infections. CLEC4M’s binding to viral glycoproteins and other pathogen molecules may prevent these pathogens from being recognized and neutralized by the immune system, as they are captured but not degraded. This mechanism allows pathogens to evade host defenses, contributing to chronic infections and immune evasion.

Therapeutic Potential in Viral Inhibition:

• Given its role in viral capture and trans-infection, CLEC4M has been considered a therapeutic target for blocking viral dissemination. Inhibitors or antibodies against CLEC4M that prevent pathogen binding could reduce viral load and limit infection spread, providing a promising avenue in antiviral strategies. Additionally, understanding CLEC4M’s role in immune regulation and pathogen interaction could lead to novel approaches for modulating immune responses in infectious and inflammatory diseases.

Summary

CLEC4M, or L-SIGN, is a C-type lectin receptor essential for pathogen recognition and immune surveillance, particularly within liver and lymph node endothelial cells. Its structure, characterized by a C-type lectin domain, extracellular stalk, and transmembrane region, allows it to capture and bind mannose-rich glycans on pathogens, mediating immune interactions and facilitating trans-infection. The ability of CLEC4M to interact with various pathogens, including viruses like SARS-CoV, HIV-1, and hepatitis C, highlights its critical role in modulating immune responses and pathogen spread within tissues.

The clinical relevance of CLEC4M extends to infectious diseases, where its ability to capture and transmit pathogens can lead to persistent infections and immune evasion. Targeting CLEC4M’s interaction with pathogens offers a potential therapeutic approach for controlling infections, especially in the liver and lymphoid tissues. As research advances, CLEC4M continues to be of interest in the study of pathogen-host interactions, immune modulation, and therapeutic strategies to manage infectious and immune-related diseases.