Programmed ribosomal frameshifting during <i>PLEKHM2</i> 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. While frameshifting is commonly used by viruses, very few phylogenetically conserved examples are known in nuclear encoded genes. Here, we report a +1 frameshifting event during decoding of the human gene <i>PLEKHM2</i> that provides access to a second internally overlapping ORF. The new carboxyl-terminal domain of this frameshift protein forms an α helix, which relieves PLEKHM2 from autoinhibition and allows it to move to the tips of cells without activation by ARL8. Reintroducing both the canonically translated and frameshifted protein are necessary to restore normal contractile function of <i>PLEKHM2</i> knockout cardiomyocytes, demonstrating the necessity of frameshifting for normal cardiac activity.

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Publication Details

Journal
Science Advances
Published
2025-10-24
DOI
https://doi.org/10.1126/sciadv.ady1742
Citations
1
Primary Topic
RNA and protein synthesis mechanisms
Type
article
Field-Weighted Citation Impact
0.81
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article

Programmed ribosomal frameshifting during PLEKHM2 mRNA decoding generates a constitutively active proteoform that supports myocardial function

Andrew E. Firth, Gary Loughran, John F. Atkins, Yousuf A. Khan et al.
1 citations
Science Advances
RNA and protein synthesis mechanisms
0.81
article

Programmed ribosomal frameshifting during PLEKHM2 mRNA decoding generates a constitutively active proteoform that supports myocardial function

Andrew E. Firth, Gary Loughran, John F. Atkins, Yousuf A. Khan, Jonathan M. Mudge, Ningyu Ding, Raffaella De Pace, Pavel V. Baranov, Irwin Jungreis, Juan S. Bonifacino, Manolis Kellis, Ji Wang, Jianchao Zhang, Xiaowei Li, Gionmattia Carancini
article en
1 citations

Abstract

Programmed ribosomal frameshifting is a process where a proportion of ribosomes change their reading frame on an mRNA. While frameshifting is commonly used by viruses, very few phylogenetically conserved examples are known in nuclear encoded genes. Here, we report a +1 frameshifting event during decoding of the human gene <i>PLEKHM2</i> that provides access to a second internally overlapping ORF. The new carboxyl-terminal domain of this frameshift protein forms an α helix, which relieves PLEKHM2 from autoinhibition and allows it to move to the tips of cells without activation by ARL8. Reintroducing both the canonically translated and frameshifted protein are necessary to restore normal contractile function of <i>PLEKHM2</i> knockout cardiomyocytes, demonstrating the necessity of frameshifting for normal cardiac activity.

Science AdvancesVol. 11(43)
Broad Institute (US), European Bioinformatics Institute (GB), Sun Yat-sen University (CN), Ollscoil na Gaillimhe – University of Galway (IE), University of Cambridge (GB), University College Cork (IE), Hereditary Disease Foundation (US), The First Affiliated Hospital, Sun Yat-sen University (CN), Eunice Kennedy Shriver National Institute of Child Health and Human Development (US), First Affiliated Hospital of Zhengzhou University (CN), Stanford University (US)
Openalex Percentile: Top 22%
RNA and protein synthesis mechanisms
0.81
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