The long noncoding RNA Malat1 contains an internal ribosome entry site mediating micropeptide translation

Abstract In most cells, Malat1 long noncoding RNA localizes to the nucleus where it affects splicing and chromatin function. In neurons Malat1 is exported to the cytoplasm where it is translated to generate the M1 micropeptide. Here we characterize an internal ribosome entry site (IRES) required for Malat1 translation. Although preceded by a long Malat1 5’ RNA segment this element induces translation at the M1 AUG. In vivo chemical probing and structural modeling identified a 135 nt RNA secondary structure consisting of three stem loops that is sufficient for IRES activity. Using this minimal element for affinity purification from cell extracts, the IRES RNA selectively binds ribosomal subunits and translation factors. Depletion of the binding proteins Rack1 and hnRNP A2/B1 inhibits downstream IRES-dependent translation without affecting translation of an upstream ORF. Our study identifies an unexpected functional unit hidden within a widely studied long noncoding RNA. Full Text Availability The license terms selected by the author(s) for this preprint version do not permit archiving in PMC. The full text is available from the preprint server.