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

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Scientists discovered programmed ribosomal frameshifting in the human gene PLEKHM2, a rare event in nuclear genes. This frameshifting is crucial for normal heart cell function.

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Area of Science:

  • Molecular Biology
  • Genetics
  • Cell Biology

Background:

  • Programmed ribosomal frameshifting is a known mechanism, primarily in viruses, for altering protein synthesis.
  • Conserved frameshifting events in nuclear-encoded genes are rare and often debated.
  • The gene PLEKHM2 plays a role in cellular processes, but its full regulatory mechanisms are not completely understood.

Purpose of the Study:

  • To investigate the phenomenon of programmed ribosomal frameshifting in the human gene PLEKHM2.
  • To characterize the mechanism and functional significance of this frameshifting event.
  • To determine the role of frameshifting in PLEKHM2's function and cellular localization.

Main Methods:

  • Analysis of mRNA sequences and ribosome behavior during translation of PLEKHM2.
  • Site-directed mutagenesis to identify the frameshifting signal.
  • Cellular localization studies using microscopy.
  • Functional assays in PLEKHM2-knockout cardiomyocytes.

Main Results:

  • A +1 programmed ribosomal frameshifting event was identified in the human PLEKHM2 gene at the conserved UCC_UUU_CGG sequence.
  • The frameshift generates a novel C-terminal domain that forms an alpha-helix, relieving autoinhibition of PLEKHM2.
  • Frameshifted PLEKHM2 associates with kinesin-1 for transport to cellular tips, independent of ARL8.
  • Restoration of both canonical and frameshifted PLEKHM2 proteins is required to rescue contractile function in knockout cardiomyocytes.

Conclusions:

  • Programmed ribosomal frameshifting is essential for PLEKHM2 function and normal cardiac activity.
  • This finding expands the known repertoire of frameshifting mechanisms in nuclear-encoded genes.
  • The frameshift-dependent regulation of PLEKHM2 impacts its localization and cellular function, particularly in cardiomyocytes.