PVR cell adhesion molecule |Elisa - Clia - Antibody - Protein

Background

PVR, also known as CD155, is a cell adhesion molecule primarily involved in cell signaling, immune modulation, and viral entry. The gene encoding this protein is found on chromosome 19q13.31, and the protein was initially identified as the receptor for poliovirus, facilitating viral entry into cells. However, PVR is not limited to viral entry functions; it plays a significant role in immune cell interactions, migration, and tissue development. Structurally part of the immunoglobulin superfamily, PVR is widely expressed in various tissues, including epithelial cells, endothelial cells, and immune cells, and is upregulated in certain cancers, suggesting an adaptive role in tumor immune escape mechanisms. This protein is a primary ligand for several immune checkpoints such as DNAM-1 (CD226), TIGIT, and CD96, highlighting its importance in immune system modulation.

Protein Structure

PVR is a type I transmembrane glycoprotein with a molecular weight of approximately 57 kDa and a structure that includes several domains:

Extracellular Domain:

• The extracellular region is critical for its binding functions and consists of three immunoglobulin-like domains: an N-terminal V-type Ig domain followed by two C2-type Ig domains.
• The V-type Ig domain is primarily responsible for interactions with immune receptors, including DNAM-1 (CD226), TIGIT, and CD96.
• Glycosylation of the extracellular region plays a role in stabilizing the protein and influencing binding affinity, particularly in modulating interactions with immune receptors. Additionally, this region is essential for poliovirus binding, facilitating viral attachment and entry.

Transmembrane Domain:

• The transmembrane domain consists of a single alpha-helix that anchors PVR in the plasma membrane, ensuring its stable presentation on the cell surface.
• This domain is responsible for positioning PVR within the membrane in such a way that its extracellular region can interact optimally with ligands and receptors on neighboring cells.

Cytoplasmic Tail:

• The cytoplasmic domain is essential for downstream signaling, particularly in cellular adhesion and motility functions. It contains motifs that can interact with cytoskeletal components and signaling molecules within the cell.
• This domain also includes sequences that regulate PVR localization within the cell membrane and determine whether the protein remains at the cell surface or is internalized.

Classification and Subtypes

PVR belongs to the immunoglobulin (Ig) superfamily, specifically within the nectin and nectin-like protein subfamily, which includes other members such as nectin-2 (CD112) and nectin-4. PVR has no direct isoforms with distinct subtypes; however, alternative splicing may produce minor variants, which can affect its functional properties and influence tissue-specific expression.

Function and Biological Significance

PVR has multiple biological functions beyond serving as a viral entry receptor. Its primary roles include modulating immune cell adhesion, promoting cell migration, facilitating immune evasion in tumors, and acting as a ligand for immune checkpoints.

Immune Modulation:

• PVR interacts with the immune checkpoint receptors DNAM-1 (CD226), TIGIT, and CD96, influencing the activation and suppression of immune responses.
• Through DNAM-1 binding, PVR promotes T cell and natural killer (NK) cell activation, leading to increased immune surveillance and cytotoxic activity against infected or transformed cells.
• Conversely, when PVR binds to TIGIT, it sends inhibitory signals that dampen immune cell activation, contributing to immune evasion in cancer by creating an immunosuppressive environment around tumor cells.

Cell Adhesion and Migration:

• PVR plays an essential role in cell-cell adhesion, where it supports interactions between epithelial and endothelial cells, maintaining tissue integrity and promoting wound healing.
• By modulating cell adhesion molecules and cytoskeletal rearrangement, PVR enhances cell migration and can promote metastasis in certain cancers. This function is particularly relevant in pathological conditions where cell motility is increased, such as in tumor invasion and metastasis.

Tumor Immune Escape:

• PVR expression is frequently upregulated in various malignancies, including melanoma, colorectal cancer, and glioblastoma. Its interaction with TIGIT in the tumor microenvironment inhibits NK and T cell responses, allowing tumor cells to escape immune destruction.
• Targeting the PVR-TIGIT pathway is an area of active research, as blocking this pathway could enhance anti-tumor immunity and improve the efficacy of immune checkpoint therapies.

Viral Receptor:

• PVR is best known for its role in mediating poliovirus entry into cells, where its V-type Ig domain binds poliovirus capsid proteins, facilitating viral endocytosis and replication.
• This role highlights PVR as a critical point of viral entry, making it a target in antiviral research aimed at blocking virus-receptor interactions.

Clinical Issues

Given its role in immune regulation, viral entry, and tumor biology, PVR is implicated in several clinical conditions:

Cancer:

• Upregulation of PVR in tumor cells is associated with poor prognosis in several cancer types due to its role in immune evasion. PVR overexpression allows tumor cells to inhibit cytotoxic T and NK cell responses, creating an immunosuppressive environment favorable for tumor growth and metastasis.
• Targeted therapies, including monoclonal antibodies against TIGIT, are under development and aim to restore immune function by disrupting the PVR-TIGIT interaction.

Autoimmune Diseases:

• Dysregulated PVR expression can contribute to autoimmune conditions by altering immune checkpoints, potentially leading to excessive immune activation and tissue damage. However, research on PVR's role in autoimmunity is still emerging, and it is currently a secondary focus compared to its role in cancer.

Infectious Disease:

• As the receptor for poliovirus, PVR remains a topic of interest in infectious disease research, particularly in poliovirus eradication strategies. Understanding PVR's role in viral binding and entry could aid in developing antiviral strategies targeting receptor-virus interactions.

Therapeutic Targeting:

• Given its role in cancer immune evasion, there is ongoing interest in developing PVR-targeted therapies. Anti-TIGIT antibodies, which block the immunosuppressive effects of PVR-TIGIT binding, are in clinical trials and are showing promise in enhancing anti-tumor immune responses.
• Additionally, PVR may serve as a biomarker for cancer progression and prognosis due to its elevated expression in tumors, especially those resistant to standard therapies.

Summary

PVR, or CD155, is a multifunctional cell adhesion molecule from the immunoglobulin superfamily with critical roles in immune modulation, cell adhesion, migration, and viral entry. Structurally, PVR consists of an extracellular Ig-like domain responsible for receptor binding, a transmembrane region that anchors it to the cell membrane, and a cytoplasmic domain essential for intracellular signaling. It is known for its interactions with immune checkpoint receptors like DNAM-1, TIGIT, and CD96, modulating both activating and inhibitory signals in immune cells. PVR’s expression in tumors aids in immune escape, marking it as a target for cancer immunotherapy, particularly in blocking the PVR-TIGIT interaction to promote anti-tumor immunity.