An Internal Ribosome Entry Site, or IRES, is a specialized sequence found within messenger RNA (mRNA) molecules. This RNA element provides an alternative way for cells to begin protein synthesis, known as translation. Normally, protein synthesis starts at one specific point on the mRNA, but an IRES acts as a “shortcut” for the cellular machinery responsible for protein production. This mechanism allows protein synthesis to occur when the usual method is hindered, offering cells and viruses a flexible means of gene expression.
The Usual Way Cells Make Proteins
Cells initiate protein production through cap-dependent translation initiation. This method begins with a modification at the 5′ end of the mRNA molecule, known as the 5′ cap. This cap signals where the protein-making machinery, specifically a small ribosomal subunit, should attach.
Eukaryotic initiation factors (eIFs) recognize and bind to this 5′ cap. This binding forms an initiation complex that recruits the 40S ribosomal subunit. The 40S subunit, along with other factors, moves along the mRNA, scanning from the 5′ end until it locates a start signal, usually an “AUG” codon. Once the start codon is found, the 60S ribosomal subunit joins, forming a complete 80S ribosome ready to synthesize a protein.
How IRES Changes the Rules for Protein Production
IRES elements offer a distinct mechanism for translation initiation, bypassing the 5′ cap of the conventional pathway. Instead of starting at the mRNA’s beginning, IRES sequences allow ribosomes to bind directly to an internal location. This direct binding is facilitated by the IRES sequence folding into a specific three-dimensional structure.
This structure recruits the 40S ribosomal subunit and other initiation factors directly to the internal site. For example, some IRES types, like those in Hepatitis C virus (HCV), can directly bind the 40S ribosomal subunit and position the initiator codon in the ribosome’s P-site without the usual scanning. Other IRES types, such as those from picornaviruses, recruit the ribosome through interactions with initiation factors like eIF4G. This alternative pathway is important when the cell’s normal cap-dependent protein synthesis is suppressed, such as during cellular stress or viral infection.
Where IRES Are Found and Why They Matter
IRES elements are found in various biological contexts, playing a role in viral replication and cellular processes.
Viral IRES elements are common in viruses like poliovirus and hepatitis C virus. These viruses exploit IRES sequences to ensure their proteins are produced, even when they shut down the host cell’s normal protein-making machinery. By using an IRES, the virus can “hijack” the host cell’s ribosomes, guaranteeing the synthesis of viral proteins necessary for replication and survival. This strategy allows the virus to thrive under conditions that would otherwise limit its ability to produce components.
Cellular IRES elements are present in eukaryotic cells and are active during stress or developmental stages. For instance, during hypoxia (low oxygen), apoptosis (programmed cell death), or nutrient starvation, cap-dependent translation can be reduced. Under these circumstances, cellular IRESs enable the continued production of proteins important for the cell’s stress response, such as those involved in cell survival or growth. Examples of proteins regulated by cellular IRESs include those involved in stress responses, cell cycle control, and growth factors.
IRES in Medicine and Research
Understanding IRES mechanisms has opened avenues for medical and research applications. Their function makes them attractive targets and tools in biotechnology.
In medicine, IRES elements represent potential targets for new therapeutic strategies, particularly in antiviral drug development. By targeting viral IRES elements, researchers aim to block the synthesis of viral proteins, inhibiting viral replication without severely affecting the host cell’s normal protein production. For example, studies have explored using small interfering RNAs (siRNAs) to suppress HCV IRES activity, leading to reduced viral protein expression in cell cultures and animal models.
IRES elements are also valuable tools in genetic engineering and biotechnology, especially in designing vectors for research or gene therapy. They can be used to express multiple proteins from a single mRNA molecule, allowing coordinated production of several genes. This is useful in gene therapy where introducing multiple genes into a cell is necessary to treat complex disorders or infectious diseases. Studying cellular IRESs can provide insights into diseases where stress responses or protein synthesis pathways are disrupted, such as cancers, neurological conditions, and cardiovascular diseases.