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

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.