IRESmediated

IRESmediated translation refers to the initiation of protein synthesis from an internal ribosome entry site within an mRNA, enabling cap independent translation. IRES elements were first discovered in the 5' untranslated regions of picornavirus genomes and were later found in cellular mRNAs, especially under conditions that impair cap dependent initiation such as cellular stress, apoptosis, or viral infection.

Mechanism and components: An IRES is a structured RNA element that can recruit ribosomes to an internal site, bypassing the need for some or all of the standard cap dependent initiation steps. Translation initiation via an IRES often requires canonical initiation factors and specialized proteins known as IRES trans acting factors ITAFs that modulate ribosome recruitment and scanning. Some IRESes are highly dependent on factors such as eIF4G and eIF3, while others can function with reduced initiation factor requirements, allowing translation when cap dependent initiation is downregulated. Viral IRESes, such as those from poliovirus and other enteroviruses, frequently promote efficient translation even after viral proteases cleave eIF4G, demonstrating distinct modes of IRES mediated initiation.

Biological significance and examples: IRES mediated translation enables selective protein synthesis during cellular stress or viral infection. In cells, certain oncogenes and survival factors—for example MYC, BCL-2, Cyclin D1, and VEGF—have IRES elements in their 5' UTRs, supporting continued production when global translation is suppressed. The hepatitis C virus provides a well studied example of an RNA element that directly recruits ribosomal subunits via the IRES, reducing reliance on several initiation factors. Regulation of ITAFs and RNA structure influences IRES activity.

Controversy and methodology: Demonstrating true IRES activity can be challenging; bicistronic reporter assays and mutational analyses are commonly used but can yield artifactual results. Ongoing work aims to catalog functional IRES elements and clarify their roles in physiology and disease.