Programmed ribosomal frameshifting duringPLEKHM2mRNA decoding generates a constitutively active mediator of kinesin-1-dependent lysosome transport

Abstract

AbstractProgrammed ribosomal frameshifting is a translational recoding phenomenon in which a proportion of ribosomes are stimulated to slip backwards or forwards on an mRNA1, rephasing the ribosome relative to the mRNA. While frameshifting is often employed by viruses2, very few phylogenetically conserved examples are known in vertebrate genes and the evidence for some of these is controversial3,4. Here we report a +1 frameshifting signal in the coding sequence of the human genePLEKHM2, encoding the ARL8-dependent, lysosome–kinesin-1 adaptor protein PLEKHM25. This +1 frameshifting signal, UCC_UUU_CGG, is highly conserved in vertebrates and exhibits an influenza virus-like frameshift motif with similar efficiency6,7. Purification and mass spectrometry of GFP-tagged trans-frame protein from cells confirms frameshifting. Structure prediction shows that the new C-terminal domain generated by this frameshift forms an alpha-helix. This additional domain relieves PLEKHM2 from autoinhibition, allowing it to move to the tips of cells via association with kinesin-1 without requiring activation by ARL8. Thus, the frameshift proteoform generates a constitutively active adaptor of kinesin-1.