HuR Protein: A Key Regulator in Health and Disease
Learn how the HuR protein, a critical RNA-binding molecule, governs gene expression to maintain cellular balance or contribute to disease when its function is altered.
The HuR protein is an RNA-binding protein that regulates gene expression in human cells. After a gene is transcribed into messenger RNA (mRNA), HuR interacts with specific mRNAs to influence their stability and translation into proteins. This regulatory role places HuR at a central point in many cellular processes, making it a subject of interest for understanding both normal biology and disease.
Defining HuR Protein
Human antigen R (HuR) is a protein encoded by the ELAVL1 gene and is a member of the ELAV family of proteins. While other members of this family are found mainly in neuronal tissues, HuR is present in nearly all cell types, underscoring its broad importance. The structure of HuR contains three RNA recognition motifs (RRMs), which are specialized domains that allow the protein to bind to specific RNA sequences.
The protein is predominantly located in the cell’s nucleus, where it first encounters new mRNA molecules. A defining aspect of its function is its ability to shuttle between the nucleus and the cytoplasm. This movement allows HuR to accompany its target mRNAs to the cellular machinery for protein synthesis, influencing their fate outside the nucleus.
Mechanisms of HuR Action
The primary mechanism of HuR is its interaction with specific sequences within messenger RNA molecules. It has a high affinity for AU-rich elements (AREs), which are regions rich in adenine and uracil nucleotides. These AREs are located in the 3′-untranslated region (3′-UTR) of mRNAs, a non-coding portion that contains regulatory sequences. Many of the mRNAs that contain these elements are inherently unstable.
Upon binding to these AREs, HuR acts to stabilize the target mRNA. It shields the mRNA from the cellular machinery that would otherwise break it down. This protection extends the lifespan of the mRNA, allowing for more protein to be produced from it.
In addition to stabilization, HuR can directly influence translation, the synthesis of proteins from an mRNA template. After accompanying an mRNA to the cytoplasm, HuR can help recruit the ribosomes and other factors needed to initiate protein production. This cytoplasmic function is often performed in response to cellular signals like stress.
Physiological Significance of HuR
The regulatory functions of HuR are integrated into a wide array of normal cellular activities. A well-documented role is in the cellular stress response. When cells are exposed to stressors such as UV radiation, low oxygen levels (hypoxia), or oxidative damage, HuR helps coordinate the expression of genes needed to manage the stress.
HuR also participates in controlling the cell cycle and programmed cell death, known as apoptosis. It regulates the expression of proteins like cyclins, which drive the cell through its division cycle, and other factors that either promote or prevent cell death. This regulation ensures that cells divide properly and that damaged cells are eliminated.
Furthermore, HuR is involved in cell differentiation and in orchestrating immune responses. It achieves this by controlling the stability and translation of mRNAs for cytokines and growth factors. These signaling molecules are used by immune cells to communicate and by developing tissues to guide their formation.
HuR’s Role in Pathological Conditions
Dysregulation of HuR’s activity, location, or amount is linked to several diseases, most notably cancer. In many tumors, HuR is found at elevated levels or is predominantly in the cytoplasm. By stabilizing the mRNAs of oncogenes (genes that can cause cancer), HuR contributes to increased cell proliferation and the prevention of apoptosis in cancer cells.
The protein also supports tumor progression by promoting angiogenesis, the formation of new blood vessels, and metastasis, the spread of cancer cells. HuR upregulates the expression of factors that drive these processes. Its role also extends to making cancers resistant to therapy by stabilizing the mRNAs of proteins that protect cancer cells from chemotherapy or radiation.
Beyond cancer, HuR misregulation is implicated in chronic inflammatory and autoimmune disorders. In these conditions, HuR can contribute to sustained inflammation by increasing the stability of mRNAs for pro-inflammatory cytokines. This leads to prolonged immune responses that can cause tissue damage.
HuR as a Therapeutic Target
The frequent overexpression and pro-tumorigenic activity of HuR in various cancers have made it an attractive target for new therapies. The rationale is that inhibiting its function could simultaneously disrupt multiple pathways that cancers rely on for growth and survival. This approach offers a potential way to combat tumors that have become resistant to other treatments.
Several strategies are being explored to inhibit HuR. One focus is the development of small-molecule inhibitors designed to interfere with HuR’s ability to bind to RNA. By blocking this interaction, these molecules would prevent HuR from stabilizing the mRNAs of cancer-promoting genes, leading to their degradation and a reduction in the synthesis of their corresponding proteins.
Other therapeutic approaches aim to disrupt HuR’s shuttling from the nucleus to the cytoplasm or to interfere with its interactions with other proteins necessary for its function. Targeting a protein like HuR presents challenges because it is involved in many normal cellular processes, creating a risk of side effects. The development of highly specific inhibitors that selectively target the pathogenic activities of HuR is a goal for researchers.