Cap-independent translation is required for starvation-induced differentiation in yeast

Cellular internal ribosome entry sites ( IRESs) are untranslated segments of mRNA transcripts thought to initiate protein synthesis in response to environmental stresses that prevent canonical 5' cap-dependent translation. Although numerous cellular mRNAs are proposed to have IRESs, none has a demonstrated physiological function or molecular mechanism. Here we show that seven yeast genes required for invasive growth, a developmental pathway induced by nutrient limitation, contain potent IRESs that require the initiation factor eIF4G for cap-independent translation. In contrast to the RNA structure-based activity of viral IRESs, we show that an unstructured A-rich element mediates internal initiation via recruitment of the poly( A) binding protein ( Pab1) to the 5' untranslated region ( UTR) of invasive growth messages. A 5' UTR mutation that impairs IRES activity compromises invasive growth, which indicates that cap-independent translation is required for physiological adaptation to stress.