Proteins are complex molecules that perform a vast array of functions within living organisms, acting as the building blocks of tissues, enzymes facilitating chemical reactions, and communicators between cells. Among the many thousands of proteins in the human body, Leucine-Rich Repeat Containing 15, or LRRC15, stands out as a protein with significant, multifaceted responsibilities.
Understanding LRRC15 Protein
LRRC15 is a protein whose name, “Leucine-Rich Repeat Containing,” offers a clue to its structure, highlighting the presence of leucine-rich repeat (LRR) motifs. These motifs are common structural elements found in many proteins, often involved in protein-protein interactions. LRRC15 is classified as a transmembrane protein, meaning it spans the cell membrane. It has an extracellular domain containing 15 LRR motifs and glycosylation sites.
The human LRRC15 protein is encoded by the LRRC15 gene, located on chromosome 3 at position 3q29. Its total structure weight is approximately 64.42 kDa, with 581 modeled and deposited amino acid residues. While its expression is generally restricted in healthy tissues, it is found in specific locations. These include fibroblasts and certain immune cells. LRRC15 is also found in the placenta, skin, lymphoid tissues like the spleen, and areas of wound healing.
LRRC15 Roles in Healthy Tissues
In healthy tissues, LRRC15 contributes to several physiological processes, primarily through its involvement in cell surface interactions. Its LRR motifs mediate protein-protein interactions. LRRC15 is involved in cell adhesion, where cells attach to each other and to the surrounding extracellular matrix (ECM).
The protein’s presence in the extracellular matrix underscores its role in tissue development and remodeling. LRRC15 has been shown to bind to components of the ECM, such as fibronectin and collagen. This binding activity suggests its contribution to maintaining tissue integrity and facilitating proper cellular function in various organs. For example, LRRC15 has been linked to the regulation of osteogenic differentiation of mesenchymal stem cells, indicating a role in bone biology.
LRRC15 and Human Disease
The involvement of LRRC15 extends beyond healthy physiological functions, as it has been implicated in various disease states, particularly in cancer, fibrotic conditions, and viral infections. Its altered expression and activity contribute to disease progression and offer potential avenues for therapeutic intervention.
Cancer
In cancer, LRRC15 is frequently overexpressed within the tumor microenvironment, specifically on cancer-associated fibroblasts (CAFs). CAFs play a supportive role in tumor growth and metastasis across various cancer types, including pancreatic, lung, breast, and head and neck cancers. LRRC15 expression has also been directly observed in mesenchymal tumors such as glioblastoma, sarcomas, and melanoma.
LRRC15 contributes to tumor progression by adhering to extracellular matrix components like fibronectin and collagen, and by activating signaling pathways such as focal adhesion kinase (FAK), which promotes cell migration and adhesion. High LRRC15 expression has been linked to later tumor stages and worse treatment outcomes in ovarian cancer, suggesting its potential as a prognostic biomarker. The protein’s role in creating an immunosuppressive microenvironment by promoting certain CAF subtypes also makes it a target for novel cancer therapies. Antibody-drug conjugates (ADCs) like ABBV-085, which target LRRC15-positive cells, are being explored in clinical trials to deliver anti-cancer agents to tumors, showing promise in preclinical models against solid tumors and in preventing metastatic spread.
Fibrosis
LRRC15 also plays a role in fibrotic conditions, involving excessive tissue scarring. In diseases such as lung fibrosis, liver fibrosis, and kidney fibrosis, activated myofibroblasts are the primary cells responsible for producing abundant amounts of extracellular matrix. LRRC15 is expressed on these collagen-producing myofibroblasts, and inhibiting LRRC15 aims to reduce the activation of fibroblasts and subsequent ECM production, potentially alleviating fibrosis. Studies suggest that LRRC15 may help control the balance between fibrotic and antiviral responses in conditions like COVID-19 lung fibrosis.
Viral Infections
LRRC15 has been identified as a host factor for SARS-CoV-2, the virus responsible for COVID-19. While LRRC15 binds to the SARS-CoV-2 spike protein, particularly its receptor-binding domain (RBD), it does not act as an entry receptor for the virus. Instead, it appears to bind and sequester viral particles, immobilizing them and preventing infection of other vulnerable cells. This “trapping” mechanism suggests LRRC15 acts as an inhibitory accessory factor, potentially reducing infection and influencing disease severity.
Its expression is particularly enriched in pathological fibroblasts in COVID-19 patients and is associated with antiviral responses. The presence or absence of LRRC15 in the blood has been linked to COVID-19 severity, highlighting its potential as an indicator and a target for developing new antiviral strategies.