Polysome propensity and tunable thresholds in coding sequence length enable differential mRNA stability.

The half-life of mRNAs, as well as their translation, increases in proportion to the optimal codons, indicating a tight coupling of codon-dependent differential translation and degradation. Little is known about the regulation of this coupling. We found that the mRNA stability gain in yeast depends on the mRNA coding sequence length. Below a critical length, codon optimality fails to affect the stability of mRNAs although they can be efficiently translated into short peptides and proteins. Above this threshold length, codon optimality-dependent differential mRNA stability emerges in a switch-like fashion, which coincides with a similar increase in the polysome propensity of the mRNAs. This threshold length can be tuned by the untranslated regions (UTR). Some of these UTRs can destabilize mRNAs without reducing translation, which plays a role in controlling the amplitude of the oscillatory expression of cell cycle genes. Our findings help understand the translation of short peptides from noncoding RNAs and the translation by localized monosomes in neurons.

An AKT1-and TRIM21-mediated phosphodegron controls proteasomal degradation of HuR enabling cell survival under heat shock.

Post-transcriptional regulation by RNA-binding proteins (RBPs) is a major mode of controlling gene expression under stress conditions. The RBP HuR regulates the translation/turnover of multiple mRNAs in stress responses. HuR is degraded in response to heat stress consequent to ubiquitination of the K182 amino acid residue. We have identified TRIM21 as the E3-ubiquitin ligase causing HuR polyubiquitination at K182 and proteasomal degradation under heat shock. The S100 and E101 residues are required for binding of TRIM21 to HuR. Heat shock-induced phosphorylation of S100 is necessary for TRIM21 interaction with HuR and subsequent degradation. We identified AKT1 as the kinase which phosphorylates S100, allowing the recognition of HuR by TRIM21. Sequential phosphorylation by AKT1 and ubiquitination by TRIM21 therefore determine a "phosphodegron" in HuR that is required for regulating the cellular level of HuR under heat shock, thereby enabling a crucial adaptive mechanism allowing cell survival in response to heat stress.

The life and death of RNA across temperatures.

Temperature is an environmental condition that has a pervasive effect on cells along with all the molecules and reactions in them. The mechanisms by which prototypical RNA molecules sense and withstand heat have been identified mostly in bacteria and archaea. The relevance of these phenomena is, however, broader, and similar mechanisms have been recently found throughout the tree of life, from sex determination in reptiles to adaptation of viral RNA polymerases, to genetic disorders in humans. We illustrate the temperature dependence of RNA metabolism with examples from the synthesis to the degradation of mRNAs, and review recently emerged questions. Are cells exposed to greater temperature variations and gradients than previously surmised? How do cells reconcile the conflicting thermal stability requirements of primary and tertiary structures of RNAs? To what extent do enzymes contribute to the temperature compensation of the reaction rates in mRNA turnover by lowering the energy barrier of the catalyzed reactions? We conclude with the ecological, forensic applications of the temperature-dependence of RNA degradation and the biotechnological aspects of mRNA vaccine production.