Internal Ribosome Entry Site RNAs act in trans through an antisense sequence

SINEUPs are antisense long non-coding RNAs (lncRNAs) that increase translation of overlapping mRNAs through the activity of two domains: an embedded SINEB2 sequence UP-regulates translation (Effector Domain) while the antisense region provides target specificity (Binding Domain). In this study, we show that the invSINEB2 sequence from the natural SINEUP AS Uchl1 RNA exhibits the functions of an Internal Ribosomal Entry Site (IRES), while viral and cellular IRES sequences act as Effector Domains, promoting protein expression in trans. We demonstrate that the Stem Loop1 of AS Uchl1 SINEB2 is functionally equivalent to the IIId loop of Hepatitis C Virus IRES. The natural circ5533, a circular RNA at the c-myc locus, up-regulates the protein expression in trans of specific target mRNAs through an IRES sequence serving as Effector Domain and antisense regions as Binding Domains. This work shows a new function for embedded transposable elements in lncRNAs, proves that an IRES sequence can work in trans enhancing the translation of a target mRNA and identify a new class of regulatory circRNAs.