HAVCR1 - hepatitis A virus cellular receptor 1 |Elisa - Clia - Antibody - Protein

Background

Hepatitis A Virus Cellular Receptor 1 (HAVCR1), also known as TIM-1 (T-cell immunoglobulin and mucin domain-containing protein 1), is a receptor protein expressed primarily on the surface of kidney epithelial cells and various immune cells. It is a member of the TIM family of proteins, which includes other receptors like TIM-3 and TIM-4. HAVCR1 plays a critical role in immune regulation, cell signaling, and disease pathogenesis, particularly within inflammatory and immune-mediated conditions. Initially identified as the receptor for hepatitis A virus (HAV), HAVCR1 has since been associated with numerous physiological and pathological processes, including immune cell activation, tissue inflammation, and the regulation of T-cell responses. HAVCR1 is implicated in immune tolerance and modulation of immune responses, making it relevant in autoimmune disorders, infections, and cancer.

Protein Structure

HAVCR1 is a type I transmembrane glycoprotein with a complex structure that contributes to its diverse functions in immune modulation and cell signaling. The HAVCR1 protein structure includes:

Immunoglobulin (Ig)-like Domain:

• The extracellular N-terminal region of HAVCR1 contains an immunoglobulin variable (IgV)-like domain, which is involved in ligand binding. This IgV domain is critical for recognizing phosphatidylserine (PS) on apoptotic cells, facilitating phagocytosis by immune cells.
• The IgV domain is also the primary interaction site for hepatitis A virus, as well as other ligands involved in immune signaling.

Mucin-like Domain:

• Following the Ig-like domain, HAVCR1 contains a mucin-like domain characterized by extensive O-linked glycosylation sites. This domain is heavily glycosylated, providing the protein with structural stability, protection from proteolysis, and a large surface area for interacting with other cells and molecules.
• The mucin domain is associated with binding functions that modulate immune interactions, particularly in inflamed tissues where cell-cell adhesion is critical.

Transmembrane Domain:

• HAVCR1 has a single transmembrane domain that anchors the protein to the cell membrane, allowing it to function as a receptor that transmits signals from the extracellular environment to intracellular signaling pathways.
• The transmembrane segment is essential for maintaining HAVCR1’s position and stability within the cell membrane, facilitating interactions with ligands and other membrane proteins.

Cytoplasmic Tail with Tyrosine-based Motifs:

• The cytoplasmic domain of HAVCR1 contains tyrosine-based signaling motifs, which are responsible for initiating intracellular signaling cascades upon receptor activation. This domain is critical for transducing external signals into cellular responses, including immune cell activation and regulation.
• The intracellular tail interacts with various kinases and adaptor proteins, enabling downstream signaling pathways involved in immune modulation.

Classification and Subtypes

HAVCR1 belongs to the TIM family of receptors, which are type I transmembrane glycoproteins characterized by Ig-like domains and mucin-like regions. The TIM family includes other members such as TIM-3 and TIM-4, which have distinct but overlapping roles in immune regulation. TIM family proteins are primarily classified based on their conserved structure, particularly the IgV domain that allows for interactions with phosphatidylserine and other ligands.

There are currently no known subtypes or isoforms of HAVCR1 in humans, although alternative splicing of related TIM family members has been observed in other organisms. The specificity of HAVCR1 for certain ligands, particularly phosphatidylserine and hepatitis A virus, distinguishes it functionally within the TIM family.

Function and Biological Significance

HAVCR1 plays critical roles in both immune regulation and cell signaling, impacting various biological processes, including:

Immune Modulation:

• HAVCR1 modulates immune cell function, particularly T-cell activation and differentiation. It acts as a co-stimulatory molecule, enhancing T-cell responses to antigens and promoting T-cell proliferation.
• The receptor is also involved in regulating T-helper cell responses, including the balance between Th1 and Th2 responses. This regulation is significant in autoimmune diseases and allergies, where shifts in immune responses can contribute to pathogenesis.

Phagocytosis of Apoptotic Cells:

• By recognizing phosphatidylserine on the surface of apoptotic cells, HAVCR1 plays an essential role in the clearance of dead cells. This function is crucial for maintaining immune homeostasis and preventing inflammation caused by cell debris.
• The ability to mediate the uptake of apoptotic cells through its IgV domain allows HAVCR1 to facilitate immune tolerance, reducing the likelihood of autoimmune responses against self-antigens.

Role in Viral Entry and Immune Evasion:

• HAVCR1 is the primary receptor for hepatitis A virus (HAV) on human cells, facilitating viral entry by binding to the IgV domain. This interaction allows the virus to infect target cells, and in the context of immune cells, it can lead to altered immune responses.
• HAVCR1 has been implicated in immune evasion mechanisms used by certain viruses, which exploit the receptor to enter cells while modulating immune signaling to avoid detection.

Tissue Regeneration and Repair:

• In kidney epithelial cells, HAVCR1 is involved in tissue repair processes. The receptor is upregulated during kidney injury and promotes cell proliferation and survival, facilitating the recovery of damaged tissues.
• HAVCR1’s expression is also associated with fibrotic processes, particularly in chronic kidney disease and liver fibrosis, where it can influence the extent of tissue repair and scarring.

Clinical Issues

Autoimmune Diseases:

• HAVCR1 is associated with the pathogenesis of autoimmune diseases, including multiple sclerosis and asthma. Dysregulation of HAVCR1 expression or signaling can lead to enhanced immune responses, contributing to autoimmunity.
• Genetic variations in the HAVCR1 gene have been linked to increased susceptibility to autoimmune diseases, likely due to altered immune regulatory functions of the receptor.

Infections and Viral Diseases:

• HAVCR1’s role as the hepatitis A virus receptor makes it relevant in the pathogenesis of viral infections. It serves as an entry point for HAV, facilitating viral spread and persistence within host tissues.
• In addition to HAV, HAVCR1 has been implicated in other viral infections where it may modulate immune responses, contributing to immune evasion strategies employed by viruses.

Kidney Disease:

• HAVCR1 is upregulated in kidney epithelial cells following injury and plays a role in tissue repair. However, chronic activation of HAVCR1 in kidney disease can contribute to fibrosis and tissue scarring, exacerbating disease progression in conditions like chronic kidney disease.
• HAVCR1 levels are also associated with prognosis in kidney disease patients, where higher expression is indicative of increased tissue damage and fibrosis.

Cancer:

• HAVCR1 has been implicated in cancer due to its immune-regulatory functions. In the tumor microenvironment, HAVCR1 expression on immune cells may contribute to immune evasion by tumors, allowing cancer cells to proliferate unchecked.
• Therapeutic targeting of HAVCR1 is being explored in cancer, particularly in tumors where HAVCR1-positive immune cells may suppress anti-tumor responses.

Summary

HAVCR1 (TIM-1) is a multifunctional receptor that plays a significant role in immune regulation, viral infection, tissue repair, and immune tolerance. Structurally, HAVCR1 is a type I transmembrane protein with an extracellular IgV-like domain, a mucin-like domain, a transmembrane region, and a cytoplasmic tail, each contributing to its complex functionality. HAVCR1’s primary roles include modulating immune responses, facilitating phagocytosis of apoptotic cells, mediating viral entry, and supporting tissue repair in epithelial tissues.

HAVCR1’s involvement in immune responses makes it relevant in the context of autoimmune diseases, where it can influence T-cell activation and immune homeostasis. It is also a critical factor in viral pathogenesis, as it serves as a receptor for hepatitis A virus, facilitating viral entry into host cells. In chronic kidney disease and fibrosis, HAVCR1 contributes to tissue repair but may also exacerbate scarring when persistently activated. Additionally, its immunomodulatory function is exploited in the tumor microenvironment, where HAVCR1-positive immune cells can suppress anti-tumor immunity.

Due to its wide-ranging functions, HAVCR1 is a therapeutic target in several disease contexts, from autoimmune disorders to cancer. Ongoing research aims to develop therapies that modulate HAVCR1 activity, either by enhancing its role in immune tolerance or inhibiting its expression in disease states where it contributes to pathology.