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Ribosome collisions trigger cis-acting feedback inhibition of translation initiation.
Translation of aberrant mRNAs can cause ribosomes to stall, leading to collisions with trailing ribosomes. Collided ribosomes are specifically recognised by ZNF598 to initiate protein and mRNA quality control pathways. Here we found using quantitative proteomics of collided ribosomes that EDF1 is a ZNF598-independent sensor of ribosome collisions. EDF1 stabilises GIGYF2 at collisions to inhibit translation initiation in cis via 4EHP. The GIGYF2 axis acts independently of the ZNF598 axis, but each pathway's output is more pronounced without the other. We propose that the widely conserved and highly abundant EDF1 monitors the transcriptome for excessive ribosome density, then triggers a GIGYF2-mediated response to locally and temporarily reduce ribosome loading. Only when collisions persist is translation abandoned to initiate ZNF598-dependent quality control. This tiered response to ribosome collisions would allow cells to dynamically tune translation rates while ensuring fidelity of the resulting protein products
TTC5 mediates autoregulation of tubulin via mRNA degradation
Tubulins play crucial roles in cell division, intracellular traffic, and cell shape. Tubulin concentration is autoregulated by feedback control of messenger RNA (mRNA) degradation via an unknown mechanism. We identified tetratricopeptide protein 5 (TTC5) as a tubulin-specific ribosome-associating factor that triggers cotranslational degradation of tubulin mRNAs in response to excess soluble tubulin. Structural analysis revealed that TTC5 binds near the ribosome exit tunnel and engages the amino terminus of nascent tubulins. TTC5 mutants incapable of ribosome or nascent tubulin interaction abolished tubulin autoregulation and showed chromosome segregation defects during mitosis. Our findings show how a subset of mRNAs can be targeted for coordinated degradation by a specificity factor that recognizes the nascent polypeptides they encode.</p
Dph7 Catalyzes a Previously Unknown Demethylation Step in Diphthamide Biosynthesis
Present on archaeal
and eukaryotic translation elongation factor
2, diphthamide represents one of the most intriguing post-translational
modifications on proteins. The biosynthesis of diphthamide was proposed
to occur in three steps requiring seven proteins, Dph1–7, in
eukaryotes. The functional assignments of Dph1–5 in the first
and second step have been well established. Recent studies suggest
that Dph6 (yeast YLR143W or human ATPBD4) and Dph7 (yeast YBR246W
or human WDR85) are involved in the last amidation step, with Dph6
being the actual diphthamide synthetase catalyzing the ATP-dependent
amidation reaction. However, the exact molecular role of Dph7 is unclear.
Here we demonstrate that Dph7 is an enzyme catalyzing a previously
unknown step in the diphthamide biosynthesis pathway. This step is
between the Dph5- and Dph6-catalyzed reactions. We demonstrate that
the Dph5-catalyzed reaction generates methylated diphthine, a previously
overlooked intermediate, and Dph7 is a methylesterase that hydrolyzes
methylated diphthine to produce diphthine and allows the Dph6-catalyzed
amidation reaction to occur. Thus, our study characterizes the molecular
function of Dph7 for the first time and provides a revised diphthamide
biosynthesis pathway