The Y-box binding protein 1 (YBX1) is found in nearly all human cells, encoded by the YBX1 gene on human chromosome 1. It is a highly conserved protein, meaning its structure and function have remained similar across many different species throughout evolution.
YBX1 functions as both a DNA and RNA binding protein, participating in a wide array of cellular processes. Its involvement in fundamental biological activities makes it a subject of scientific investigation, providing insights into how cells operate and how these processes can go awry in disease.
The Many Jobs of YBX1
YBX1 is a multifunctional protein with diverse roles that maintain cellular health and proper functioning. It plays a part in gene expression and regulation, influencing which genes are active or inactive within a cell. This control is partly achieved by binding to specific DNA sequences known as Y-boxes in gene promoters, like those found in the MDR1 gene.
The protein is also involved in RNA metabolism, which includes the processing, transport, and stabilization of RNA molecules. YBX1 helps regulate pre-mRNA alternative splicing, ensuring that messenger RNA (mRNA) is correctly assembled for protein synthesis. It also stabilizes cytoplasmic mRNA and influences translation by interacting with eukaryotic initiation factors.
Beyond its roles in gene expression, YBX1 contributes to DNA repair, maintaining the integrity of the cell’s genetic material. It can promote the separation of DNA strands containing mismatches or those modified by certain compounds, such as cisplatin. YBX1 also exhibits endonucleolytic activity, meaning it can introduce nicks or breaks into double-stranded DNA, and it participates in mitochondrial DNA mismatch repair.
YBX1 helps cells respond to cellular stress, such as oxidative stress and DNA damage. Under stress conditions, YBX1 can contribute to the formation of stress granules, which are cytoplasmic structures where untranslated mRNAs are temporarily stored. It also translocates to the nucleus following DNA damage to participate in repair mechanisms, thereby enhancing cell survival.
When YBX1 Goes Awry
When the normal regulation or activity of YBX1 is disrupted, it can contribute to the development and progression of various diseases. In cancer, YBX1 is often found in elevated levels or exhibits abnormal activity across many tumor types. Its overexpression promotes tumor growth by enhancing the expression of genes involved in cell proliferation, such as EGFR, HER2, and cyclins.
YBX1 also plays a role in metastasis, the spread of cancer cells. It promotes cancer cell invasion and is associated with poor prognosis in multiple cancers, including breast cancer and gastric cancer. The protein contributes to chemotherapy resistance by dysregulating genes like ABCB1, involved in multidrug resistance, and by affecting pathways that reduce treatment susceptibility.
In addition to cancer, YBX1 is involved in inflammatory processes and autoimmune conditions. Its dysregulation has been linked to chronic inflammation, where it modulates signaling pathways that drive inflammatory phenotypes. This suggests a broader role in immune modulation and maintaining immune system balance.
The protein also influences the life cycle of certain viruses. For example, YBX1 is a cellular factor for the replication of multiple alphaviruses, including chikungunya virus. It promotes the binding of viral genomic RNA to viral proteins, which is necessary for the assembly of viral replication complexes. YBX1 also interacts with dengue virus nucleocapsid, playing a part in the assembly and secretion of infectious viral particles.
Targeting YBX1 for Health
Given its involvement in various diseases, particularly cancer, YBX1 has emerged as a potential target for new diagnostic and therapeutic strategies. Researchers are exploring ways to inhibit its activity, especially in cancer therapy. Inhibiting YBX1 can lead to decreased cell proliferation and increased apoptosis in many cancer cell lines, including ovarian cancer, renal cell carcinoma, and colon cancer.
Small molecule inhibitors are being investigated to block YBX1’s activity. For instance, SU056 has been shown to inhibit ovarian cancer cell proliferation and can sensitize these cells to chemotherapy drugs like paclitaxel. Fisetin, another small molecule, can inhibit the interaction between AKT and YBX1, impacting cancer cell growth and epithelial-mesenchymal transition.
Beyond direct inhibition, strategies to modulate YBX1’s function are also being explored. This includes understanding how post-translational modifications, such as phosphorylation, affect its activity and subcellular location. For example, phosphorylation at serine 102 is linked to YBX1’s nuclear translocation and oncogenic activation, providing a specific target for intervention.
YBX1 also holds promise as a diagnostic biomarker. Its elevated expression is associated with poor prognosis in many cancers and can correlate with treatment response. This suggests its potential use in predicting disease progression or identifying patients who might benefit from YBX1-targeted therapies.