Programmed ribosomal frameshifting during PLEKHM2 mRNA decoding generates a constitutively active mediator of kinesin-1-dependent lysosome transport

Khan, Y. A.; De Pace, R.; Jungreis, I.; Carancini, G.; Mudge, J. M.; Kellis, M.; Atkins, J. F.; Baranov, P.; Firth, A.; Bonifacino, J.; Loughran, G.

doi:10.1101/2024.08.30.610563

bioRxiv · 10.1101/2024.08.30.610563

Programmed ribosomal frameshifting during PLEKHM2 mRNA decoding generates a constitutively active mediator of kinesin-1-dependent lysosome transport

Khan, Y. A.·De Pace, R.·Jungreis, I.·Carancini, G.·Mudge, J. M.·Kellis, M.·Atkins, J. F.·Baranov, P.·Firth, A.·Bonifacino, J.·Loughran, G.

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Abstract

Programmed ribosomal frameshifting is a process where a proportion of ribosomes change their reading frame on an mRNA1, rephasing the ribosome relative to the mRNA. While frameshifting is commonly employed by viruses2, very few phylogenetically conserved examples are known in nuclear encoded genes and some of the evidence is controversial3,4. Here we report a +1 frameshifting event during decoding of the human gene PLEKHM25. 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 efficiency6,7. The new C-terminal domain generated by this frameshift forms an -helix, which relieves PLEKHM2 from autoinhibition and allows it to move to the tips of cells via 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 PLEKHM2-knockout cardiomyocytes, demonstrating the necessity of frameshifting for normal cardiac activity.

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Khan, Y. A., De Pace, R., Jungreis, I., Carancini, G., Mudge, J. M., Kellis, M., Atkins, J. F., Baranov, P., Firth, A., Bonifacino, J., Loughran, G.. 2024-08-31. Programmed ribosomal frameshifting during PLEKHM2 mRNA decoding generates a constitutively active mediator of kinesin-1-dependent lysosome transport. https://doi.org/10.1101/2024.08.30.610563

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