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Structural basis of mRNA decay by the human exosome-ribosome supercomplex

Alexander Kögel1, Achim Keidel1, Matina-Jasemi Loukeri1

  • 1Department of Structural Cell Biology, Max Planck Institute of Biochemistry, Martinsried, Germany.

Nature
|October 9, 2024
PubMed

Insights

The cytoplasmic exosome and ribosome form a supercomplex for mRNA decay. This structure directly couples the SKI2 helicase to the exosome, threading RNA for degradation during translation.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Biochemistry

Background:

  • Translation and mRNA decay are linked in human cells.
  • The cytoplasmic exosome, including EXO10 and SKI2, degrades mRNA associated with ribosomes.
  • The bridging factor HBS1L3 (SKI7) is thought to mediate mRNA transfer, but the mechanism is unclear.

Purpose of the Study:

  • To elucidate the mechanism of mRNA handover from translating ribosomes to the cytoplasmic exosome.
  • To determine how the EXO10 exoribonuclease is recruited to the ribosome-bound SKI2 helicase complex.
  • To reveal the structural basis of co-translational mRNA decay.

Main Methods:

  • Cryo-electron microscopy to capture the structure of the exosome-ribosome supercomplex.
  • Biochemical assays to study protein-protein and protein-RNA interactions.
  • Structural analysis of the SKI2 helicase, EXO10 exoribonuclease, and HBS1L3 (SKI7) bridging factor.

Main Results:

  • A direct physical coupling mechanism, not a sequential handover, recruits EXO10 to the ribosome-bound SKI2 complex via HBS1L3 (SKI7).
  • A stable cytoplasmic exosome-ribosome supercomplex is formed, enabling co-translational mRNA decay.
  • Structural data reveals a continuous path for RNA threading from the ribosome, through SKI2 helicase, into the exosome's active site.
  • The SKI3 subunit bridges HBS1L3 (SKI7) and the ribosome's 40S subunit, creating a platform for decay.

Conclusions:

  • The exosome and ribosome function as a single unit in co-translational mRNA decay.
  • This supercomplex formation coordinates mRNA degradation with ongoing translation.
  • The findings clarify a key step in mRNA quality control pathways.

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