LY6 gene

The LY6E gene (LY6E stands for: lymphocyte antigen 6 family member E) is a protein-coding gene located on chromosome 8q24.3. An important paralog of this gene is GPIHBP1. This gene belongs to the human Ly6 gene family and encodes a glycosylphosphatidyl inositol (GPI)-anchored cell surface protein. The protein plays an important role in T cell physiology, oncogenesis and immunological regulation. The protein is also involved in the modulation of viral infection by coronaviruses, SARS-CoV, MERS-CoV and SARS-CoV-2.

The GPI-anchored cell surface protein regulates the proliferation, differentiation and activation of T lymphocytes. It further regulates T cell receptor(TCR) signaling by interacting with the CD3Z/CD247 component at the plasma membrane, resulting in modulation of CD3Z/CD247 phosphorylation. The GPI-anchored cell surface protein restricts the entry of human coronaviruses, including SARS-CoV, MERS-CoV and SARS-CoV-2, by interfering with membrane fusion mediated by the spike protein (Hackett BA et al. 2018).

It also plays an essential role in placenta formation by acting as a major receptor for syncytin-A (SynA). Therefore, it is involved in the normal fusion of syncytiotrophoblast layer I (SynT-I) and in the proper morphogenesis of both the fetal and maternal vasculature within the placenta.

May also act as a modulator of the activity of nicotinic acetylcholine receptors (nAChRs).

Furthermore, the encoded protein promotes the entry of various viruses, including HIV-1, West Nile virus, dengue virus and Zika virus, probably through an enhanced virus-cell fusion process (Yu J et al. 2017). In contrast, paramyxovirus PIV5, which invades at the plasma membrane, does not require LY6E (Hackett BA et al. 2018).

Mechanistically, it adopts a microtubule-like organization after viral infection and promotes virus unpacking after escape from the endosome (Mar KB et al. 2018).

Diseases associated with the LY6E gene include acute promyelocytic leukemia and T-cell non-Hodgkin's lymphoma. High expression of LY6 genes has been shown to be associated with OS and disease-free survival in pancreatic cancer (DFS). The high expression of LY6 genes and its association with OS outcome depends on the composition of the tumor microenvironment. Considering that LY6 proteins are anchored to the outer cell membrane or secreted, making them easily accessible, these findings highlight the potential of LY6 family members for the future diagnosis and treatment of pancreatic cancer (Russ E et al. 2021).

1. Hackett BA et al. (2018) Flavivirus internalization is regulated by a size-dependent endocytic pathway. Proc Natl Acad Sci U S A 115:4246-4251.
2. Mar KB et al. (2018) LY6E mediates an evolutionarily conserved enhancement of virus infection by targeting a late entry step. Nat Commun 9:3603.
3. Russ E et al. (2021) High mRNA expression of LY6 gene family is associated with overall survival outcome in pancreatic ductal adenocarcinoma. Oncotarget 12:145-159.
4. Yu J et al. (2017) Interferon-inducible LY6E protein promotes HIV-1 infection. J Biol Chem 292:4674-4685.