Translation Inhibitory Elements from Hoxa3 and Hoxa11 mRNAs use uORFs for translation inhibition

During embryogenesis, Hox mRNA translation is tightly regulated by a
sophisticated molecular mechanism that combines two RNA regulons located
in their 5’UTR. First, an Internal Ribosome Entry Site (IRES) enables
cap-independent translation. The second regulon is a Translation
Inhibitory Element or TIE, which ensures concomitant cap-dependent
translation inhibition. In this study, we deciphered the molecular
mechanisms of mouse Hoxa3 and a11 TIE elements. Both TIEs possess an
upstream Open Reading Frame (uORF) that is critical to inhibit
cap-dependent translation. However, the molecular mechanisms used are
different. In TIE a3, we identify a uORF which inhibits cap-dependent
translation and we show the requirement of the non-canonical initiation
factor eIF2D for this process. The mode of action of TIE a11 is different,
it also contains a uORF but it is a minimal uORF formed by an uAUG
followed immediately by a stop codon, namely a ‘start-stop’. The 
‘start-stop’ sequence is species-specific and in mice, is located upstream
of a highly stable stem loop structure which stalls the 80S ribosome and
thereby inhibits cap-dependent translation of Hox a11 main ORF.