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Cited by 25RNA Research and SplicingRNA and protein synthesis mechanismsExtracellular vesicles in disease

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

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Kögel, Alexander, Keidel, Achim, Loukeri, Matina-Jasemi, Kuhn, Christopher C., Langer, Lukas M., Schäfer, Ingmar B., Conti, Elena·2024·Nature
DOI 10.1038/s41586-024-08015-6PMC PMC11540850
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Abstract

The interplay between translation and mRNA decay is widespread in human cells 1–3 . In quality-control pathways, exonucleolytic degradation of mRNA associated with translating ribosomes is mediated largely by the cytoplasmic exosome 4–9 , which includes the exoribonuclease complex EXO10 and the helicase complex SKI238 (refs. 10–16 ). The helicase can extract mRNA from the ribosome and is expected to transfer it to the exoribonuclease core through a bridging factor, HBS1L3 (also known as SKI7), but the mechanisms of this molecular handover remain unclear 7,17,18 . Here we reveal how human EXO10 is recruited by HBS1L3 (SKI7) to an active ribosome-bound SKI238 complex. We show that rather than a sequential handover, a direct physical coupling mechanism takes place, which culminates in the formation of a cytoplasmic exosome–ribosome supercomplex. Capturing the structure during active decay reveals a continuous path in which an RNA substrate threads from the 80S ribosome through the SKI2 helicase into the exoribonuclease active site of the cytoplasmic exosome complex. The SKI3 subunit of the complex directly binds to HBS1L3 (SKI7) and also engages a surface of the 40S subunit, establishing a recognition platform in collided disomes. Exosome and ribosome thus work together as a single structural and functional unit in co-translational mRNA decay, coordinating their activities in a transient supercomplex.

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Authors
Kögel, A., Keidel, A., Loukeri, M.-J., Kuhn, C. C., Langer, L. M., Schäfer, I. B., & Conti, E.
Affiliations
Max Planck Institute of Biochemistry (DE)
Corresponding author
  • Schäfer, Ingmar B.
  • Conti, Elena
ORCID
Venue
Nature
Publisher
Springer Science and Business Media LLC
Published
2024-10-09
Volume
635
Issue
8037
Pages
237-242
ISSN
  • 0028-0836 (ISSN-L)
  • 1476-4687
DOI
10.1038/s41586-024-08015-6
PMC
PMC11540850
OpenAlex
W4403244153
Cited by
25
References
57
Citations by year
2026: 16 · 2025: 8 · 2024: 1
FWCI
3.40
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
Funders
Max-Planck-Gesellschaft
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Extracellular vesicles in disease
Keywords
mRNA degradation, exosomes, ribosome, exonucleolytic degradation, 80S ribosome, 40S ribosomal subunit, protein complex structure
MeSH terms
Cytoplasm, DNA Helicases, Exoribonucleases, Humans, Models, Molecular, Protein Binding, Ribosomes, RNA, Messenger, Protein Biosynthesis, HSP70 Heat-Shock Proteins, GTP-Binding Proteins, Cryoelectron Microscopy, RNA Helicases, RNA Stability, Exosomes, Exosome Multienzyme Ribonuclease Complex

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