Secondary RNA structure and nucleotide specificity contribute to internal initiation mediated by the human tau 5' leader.

Mechanisms by which eukaryotic internal ribosomal entry sites (IRESs) initiate translation have not been well described. Viral IRESs utilize a combination of secondary/tertiary structure concomitant with sequence specific elements to initiate translation. Eukaryotic IRESs are proposed to utilize the same components, although it appears that short sequence specific elements are more common. In this report we perform an extensive analysis of the IRES in the human tau mRNA. We demonstrate that the tau IRES exhibits characteristics similar to viral IRESs. It contains two main structural domains that exhibit secondary interactions, which are essential for internal initiation. Moreover, the tau IRES is extremely sensitive to small nucleotide substitutions. Our data also indicates that the 40S ribosome is recruited to the middle of the IRES, but whether it scans to the initiation codon in a linear fashion is questioned. Overall, these results identify structural and sequence elements critical for tau IRES activity and consequently, provide a novel target to regulate tau protein expression in disease states including Alzheimer disease and other tauopathies.