Panel A: An illustration showing the effects of ribosome defects on mRNA degradation and protein production. Top: Normal ribosomes collide at stall sequences, leading to mRNA degradation. Bottom: Defective ribosomes fail to degrade mRNA, increasing protein production. Panel B: Diagrams illustrating nascent protein folding in ribosome exit channels. Top: Efficient folding in standard ribosomes. Bottom: Specialized ribosomes required for correct folding, with misfolded proteins being degraded. Panel C: Diagrams depicting the impact of upstream open reading frames (uORFs) on downstream ORF translation. Top: uORFs inhibit downstream ORF translation. Bottom: Defective ribosomes lead to leaky scanning and potential translation of downstream ORFs.
Mechanisms by which ribosome heterogeneity might affect translation in an mRNA-specific manner. (A) Top: Defects in mRNAs or specific stall sequences (shown in orange on the mRNA), lead to stalling of the ribosome and collision of the trailing ribosome. The collided interface is recognized to assemble a complex, which ultimately degrades the bound mRNA (D’Orazio and Green, 2021; Filbeck et al., 2022; Kim and Zaher, 2022; Meydan and Guydosh, 2021). Bottom: specialized (or defective) ribosomes with mutations at the collided interface fail to degrade the mRNAs with stalling sequences, leading to the increased production of proteins from such mRNAs. (B) Top: Some nascent proteins fold efficiently in exit channels of standard ribosomes. Bottom: Other nascent proteins require specialized ribosome channels for correct co-translational folding. Misfolded proteins are degraded. (C) Top: translation of upstream ORFs (uORFs, dark blue) often inhibits the translation of the downstream ORF (cyan). Bottom: Ribosomes with defects at the subunit interface (in orange) are expected to be prone to leaky scanning, if the time it takes for subunit joining is too long.