PVRL1

Fig1. Homophilic (black arrow) and heterophilic (red arrow) interactions among nectins are shown at the center. (Dibyendu Samanta, 2015)

What is PVRL1 protein?

PVRL1 (NECTIN1, nectin cell adhesion molecule 1) gene is a protein coding gene which situated on the long arm of chromosome 11 at locus 11q23. This gene encodes an adhesion protein that plays a role in the organization of adherens junctions and tight junctions in epithelial and endothelial cells. The protein is a calcium(2+)-independent cell-cell adhesion molecule that belongs to the immunoglobulin superfamily and has 3 extracellular immunoglobulin-like loops, a single transmembrane domain (in some isoforms), and a cytoplasmic region. This protein acts as a receptor for glycoprotein D (gD) of herpes simplex viruses 1 and 2 (HSV-1, HSV-2), and pseudorabies virus (PRV) and mediates viral entry into epithelial and neuronal cells. PVRL1 protein is consisted of 517 amino acids and its molecular mass is approximately 57.2 kDa.

What is the function of PVRL1 protein?

PVRL1 is involved in the formation and maintenance of cell-cell adhesion, which is crucial for tissue integrity and cell signaling. It contributes to the organization of adherens junctions and tight junctions in epithelial and endothelial cells, which are essential for maintaining the barrier function of these cells. PVRL1 is implicated in the regulation of immune cell functions. It interacts with other proteins like PVR (poliovirus receptor) and TIGIT (T cell immunoreceptor with Ig and ITIM domains), which are involved in modulating immune responses. PVRL1 has also been linked to developmental processes, including the formation of the nervous system and the development of the heart and face, with mutations in the PVRL1 gene potentially contributing to conditions like non-syndromic cleft lip.

PVRL1 Related Signaling Pathway

PVRL1 is involved in the formation of intercellular connections by interacting with adhesion molecules on the surface of other cells, such as other members of the Nectin family, which is essential for maintaining tissue structure and cell polarity. PVRL1 interacts with TIGIT receptors on immune cells, and this interaction can inhibit the activation and proliferation of T and NK cells, thereby playing a role in regulating immune responses. PVRL1, together with PVR and PVRL2, forms a co-stimulatory network involving multiple immune checkpoint receptors, such as DNAM-1, that play a role in regulating the activity of T and NK cells.

PVRL1 Related Diseases

PVRL1 is up-regulated in certain types of cancer, such as hepatocellular carcinoma (HCC). Studies have shown that liver cancer cells regulate PVRL1 to stabilize PVR on the cell surface and interact with TIGIT molecules to inhibit anti-tumor immune response of CD8+ effector memory T cells, thereby mediating tumor resistance to PD-1 inhibitors. PVRL1, as a viral receptor, is involved in the cellular invasion of viruses such as herpes simplex virus (HSV) and Pseudorabies virus (PRV). Some studies have investigated the relationship between PVRL1 gene SNP and environment interaction and non-syndromic cleft lip and palate. Loss of TIGIT can lead to a severe autoimmune disease phenotype in mice, suggesting that the PVRL1-TIGIT axis may play a role in autoimmune regulation.

Bioapplications of PVRL1

Using purified PVRL1 proteins, researchers can carry out protein engineering to improve its function or confer new properties by modifying the structure of PVRL1, which has potential applications in fields such as enzyme preparations and biocatalysis. Purified PVRL1 proteins are used to develop diagnostic tools for specific diseases. For example, by detecting PVRL1 levels in patient samples, doctors may be able to diagnose or monitor disease progression associated with abnormal PVRL1 expression. With the development of precision medicine, purified PVRL1 proteins may play a role in the development of personalized treatment regimens. By accurately measuring a patient's PVRL1 level, doctors can provide a more customized treatment plan for their patients.

Case Study 1: Joanne Kite, 2024

A multitude of viruses reduce the expression of their corresponding receptors, which helps in their replication and disease progression through mechanisms that are still not completely clear. While some research indicates that gD alone from the virus is enough to downregulate nectin1, the viral protein ICP0, an E3 ubiquitin ligase, has also been suggested to play a role. In this study, the researchers utilized nTERT human keratinocytes, a cell type that they have established to naturally express significant amounts of nectin1, to thoroughly examine the changes in nectin1 levels during HSV1 infection. They observed that nectin1, unlike nectin2 or the transferrin receptor, was removed from the cell surface in a process that was dependent on the synthesis of viral proteins and not on the incoming virus particles themselves. This process was also not a result of the virus-induced shutdown of host protein synthesis. Importantly, gD was found to be necessary and alone sufficient to cause the depletion of nectin1, suggesting that no additional viral proteins are required for this effect. Lastly, our experiments showed that the capacity of HSV1 to prevent further infection, as measured by the infection with a GFP-expressing HSV1, was reliant on gD and coincided with the timing of nectin1 downregulation, highlighting the critical role of gD in this antiviral strategy.

Fig1. Nectin1 expression was analysed by flow cytometry.

Fig2. Downregulation of nectin1 in HSV1-infected cells is not a consequence of host shutoff.

Case Study 2: Vaibhav Tiwari, 2008

Herpes simplex virus 1 (HSV-1) has the distinctive capacity to infect a broad spectrum of host cells. The retinal pigment epithelial (RPE) cells, which constitute the retina's outer layer, are vulnerable to viral infection, potentially leading to lasting damage to vision. In this study, the researchers scrutinize the preliminary cellular and molecular processes that enable HSV-1 to penetrate human RPE cells. Utilizing RT-PCR, the researchers identified the presence of nectin-1, herpes virus entry mediator (HVEM), and 3-O-sulfotransferase-3, which serves as an indicator for 3-O-sulfated heparan sulfate. The expression of HVEM and nectin-1 was further confirmed through flow cytometry. Immunohistochemical analysis also confirmed nectin-1 expression in mouse retinal tissues. Notably, antibodies targeting nectin-1, and not HVEM, were capable of inhibiting HSV-1 infection. The use of small interfering RNA (siRNA) specifically designed to target nectin-1 similarly hindered infection and also prevented cell fusion with HSV-1 glycoprotein-expressing Chinese hamster ovary (CHO-K1) cells. Both anti-nectin-1 antibodies and agents that depolymerize F-actin were effective in impeding the cytoskeletal rearrangements that accompany HSV-1 cell entry.

Fig3. Cell surface expression of nectin-1 in cultured RPE cells by fluorescence-activated cell sorter (FACS) analysis.

Fig4. Cell surface expression of nectin-1 in RPE cells is downregulated by the siRNA.

PVRL1 has several biochemical functions, for example, carbohydrate binding,cell adhesion molecule binding,coreceptor activity. Some of the functions are cooperated with other proteins, some of the functions could acted by PVRL1 itself. We selected most functions PVRL1 had, and list some proteins which have the same functions with PVRL1. You can find most of the proteins on our site.

PVRL1 has direct interactions with proteins and molecules. Those interactions were detected by several methods such as yeast two hybrid, co-IP, pull-down and so on. We selected proteins and molecules interacted with PVRL1 here. Most of them are supplied by our site. Hope this information will be useful for your research of PVRL1.

PVRL4;PVRL3;vgld_hhv1f_protein;Pick1;MLLT4;gD