Programmed ribosomal frameshifting during mRNA decoding generates a constitutively active proteoform that supports myocardial function.

Programmed ribosomal frameshifting is a process where a proportion of ribosomes change their reading frame on an mRNA, rephasing the ribosome relative to the mRNA. While frameshifting is commonly employed by viruses, very few phylogenetically conserved examples are known in nuclear encoded genes and some of the evidence is controversial. Here we report a +1 frameshifting event during decoding of the human gene . This frameshifting occurs at the sequence UCC_UUU_CGG, which is conserved in vertebrates and is similar to an influenza virus sequence that frameshifts with similar efficiency. The new C-terminal domain generated by this frameshift forms an α-helix, which relieves PLEKHM2 from autoinhibition and allows it to move to the tips of cells association with kinesin-1 without requiring activation by ARL8. Reintroducing both the canonically-translated and frameshifted protein are necessary to restore normal contractile function of -knockout cardiomyocytes, demonstrating the necessity of frameshifting for normal cardiac activity.