The Lupus autoantigen La is an RNA-binding protein that stabilizes RNA polymerase III (Pol III) transcripts and supports correct RNA folding. In addition, La was shown to affect the biogenesis of mammalian microRNAs (miRNAs).
In this study, we have analyzed the consequences of La depletion on the Argonaute (Ago)-bound small RNA (sRNA) population in human cells. We find that in the absence of La, distinct tRNA fragments are loaded into Ago proteins. Thus, La functions as gatekeeper ensuring correct tRNA maturation and thereby protects the cell from tRNA fragments, which might be potentially harmful by acting as unintended miRNAs.
We further provide evidences, that viral non-coding RNAs (ncRNAs) perturb La’s gatekeeper function and induce the production of Ago-loaded tRNA fragments, mimicking the effects observed under La depletion.
Interestingly, one specific isoleucine precursor tRNA (pre-tRNA) produces both, a tRNA and a functional miRNA, even when La is present. We demonstrate that this specific pre-tRNA is able to partially escape from La binding due to its fully complementary 5’ leader and 3’ trailer sequences. The double-stranded RNA structure of this specific isoleucine pre-tRNA reduces the affinity to La and allows processing by components of the miRNA biogenesis machinery.
In sum, our study unraveled a novel aspect of La biology, showing that it supports correct pathway selection and, by that, maturation of primary Pol III transcripts. Furthermore, we characterized in molecular detail the biogenesis of a non-canonical, pre-tRNA-derived miRNA
