Ribosomal Protein 6 Phosphorylation Regulates Translational Responses to Dietary Restriction

Forms of dietary restriction like intermittent fasting (IF) and caloric restriction (CR) promote health and longevity through changes in gene expression. While the transcriptional changes that occur in response to DR have been well described across several species, the role of translational regulation has lagged. Using polysome profiling and mRNA-seq, we quantified changes in actively translated mRNAs that occur in C. elegans under CR compared to well-fed conditions. The analysis revealed hundreds of transcripts regulated on the translational level that would have been missed using conventual transcriptomics. Among the translationally down-regulated genes that where pro-longevity when knocked down were regulators of the cell-cycle: fbxb-24, sdz-33, kbp-1, and cdk-2. In search of the mechanisms regulating selective translation under CR we investigated a role for ribosomal protein 6 (RPS-6) as its phosphorylation status is thought to regulate cell cycle and selective translation of mRNA transcripts. Using RPS-6 phospho-null and phospho-mimetic mutants, we show that phosphorylation and de-phosphorylation of RPS-6 is necessary for the pro-longevity effects of CR and IF. Furthermore, we show that IF is more beneficial for retaining locomotion with age than CR and that endogenously tagged RPS-6 ::mCherry accumulates in body wall muscle under fasting. However, the benefit of IF on locomotion is lost in RPS-6 phospho-mimetic mutants. Together, results suggest that protein translation is enhanced in the muscle under IF to prevent sarcopenia in a way dependent on RPS-6. Translatome analysis of the phospho-mutant suggested a role for RPS-6 in selective translation of p38 mitogen-activated protein kinases.

The Impact of Endoplasmic Reticulum-Associated Protein Modifications, Folding and Degradation on Lung Structure and Function

The accumulation of unfolded/misfolded proteins in the endoplasmic reticulum (ER) causes ER stress and induces the unfolded protein response (UPR) and other mechanisms to restore ER homeostasis, including translational shutdown, increased targeting of mRNAs for degradation by the IRE1-dependent decay pathway, selective translation of proteins that contribute to the protein folding capacity of the ER, and activation of the ER-associated degradation machinery. When ER stress is excessive or prolonged and these mechanisms fail to restore proteostasis, the UPR triggers the cell to undergo apoptosis. This review also examines the overlooked role of post-translational modifications and their roles in protein processing and effects on ER stress and the UPR. Finally, these effects are examined in the context of lung structure, function, and disease.

KSR1-and ERK-dependent translational regulation of the epithelial-to-mesenchymal transition

The epithelial-to-mesenchymal transition (EMT) is considered a transcriptional process that induces a switch in cells from a polarized state to a migratory phenotype. Here we show that KSR1 and ERK promote EMT-like phenotype through the preferential translation of Epithelial-Stromal Interaction 1 (EPSTI1), which is required to induce the switch from E- to N-cadherin and coordinate migratory and invasive behavior. EPSTI1 is overexpressed in human colorectal cancer (CRC) cells. Disruption of KSR1 or EPSTI1 significantly impairs cell migration and invasion in vitro, and reverses EMT-like phenotype, in part, by decreasing the expression of N-cadherin and the transcriptional repressors of E-cadherin expression, ZEB1 and Slug. In CRC cells lacking KSR1, ectopic EPSTI1 expression restored the E- to N-cadherin switch, migration, invasion, and anchorage-independent growth. KSR1-dependent induction of EMT-like phenotype via selective translation of mRNAs reveals its underappreciated role in remodeling the translational landscape of CRC cells to promote their migratory and invasive behavior.

Translational specialization in pluripotency by RBPMS poises future lineage-decisions

SUMMARYIn mammals, translation is uniquely regulated at the exit of pluripotency to rapidly reprogram the proteome to enable lineage commitment. Yet, the developmental mediators of translational control and their mode-of-action remain elusive. Using human embryonic stem cells, we identified RBPMS as a vital translation specialization factor that allows selective translation of developmental regulators. RBPMS-driven translational control balances the abundance of cell-fate regulators to enable accurate lineage decisions upon receiving differentiation cues. RBPMS loss, without affecting pluripotency, specifically and severely impedes mesoderm specification and subsequent cardiogenesis. Mechanistically, the direct binding of RBPMS to 3’UTR allows selective translation of transcripts encoding developmental regulators including integral components of central morphogen signaling networks specifying mesoderm. RBPMS-loss results in aberrant retention of key translation initiation factors on ribosomal complexes. Our data unveil how emerging lineage choices from pluripotency are controlled by translational specialization via ribosomal platforms acting as a regulatory nexus for developmental cell fate decisions.IN BRIEFFuture lineage choices from pluripotency are controlled by translational specialization. The RNA binding protein RBPMS is a vital translational specialization factor that unlocks the mesoderm commitment potential of pluripotent stem cells by enabling selective translation of cell-fate regulators instructing lineage decisions.HIGHLIGHTSLineage choices emerging from pluripotency are selectively controlled by translational specializationThe RNA-binding protein RBPMS is a translation specialization factor dedicated to mesoderm commitmentRBPMS-driven translational specialization enables accurate lineage commitment via balancing the availability of key morphogen signaling componentsRBPMS loss selectively impairs mesoderm commitment and subsequently impedes cardiogenesisRBPMS binds the 3’UTRs of target mRNAs to allow their selective translation; its depletion leads to aberrant retention of key translation initiation factors on ribosomal complexes

Modeling the SARS-CoV-2 nsp1–5’-UTR complex via extended ensemble simulations

Nonstructural protein 1 (nsp1) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a 180-residue protein that blocks translation of host mRNAs in SARS-CoV-2-infected cells. Although it is known that SARS-CoV-2’s own RNA evades nsp1’s host translation shutoff, the molecular mechanism underlying the evasion was poorly understood. We performed an extended ensemble molecular dynamics simulation to investigate the mechanism of the viral RNA evasion. Simulation results showed that the stem loop structure of the SARS-CoV-2 RNA 5’-untranslated region (SL1) is recognized by both nsp1’s globular region and intrinsically disordered region. The recognition presumably enables selective translation of viral RNAs. Cluster analysis of the binding mode and detailed analysis of the binding poses revealed several residues involved in the SL1 recognition mechanism. The simulation results imply that the nsp1 C-terminal helices are lifted from the 40S ribosome upon the binding of SL1 to nsp1, unblocking translation of the viral RNA.

Translating the English academic article for a French readership in 1686

Previous studies of translations from the Philosophical Transactions to the Journal des Sçavans in 1665 and 1675 showed that the translators adopted a strategy of selective translation. The present study looks at five examples published in 1686. Selective translation is again in evidence. Analyses of thematic structure and process types, however, show only slight differences, but with biases towards constant progression and material processes in the French versions. It is suggested that this can be explained by the translator adapting his texts to his readership. Whereas the Philosophical Transactions was restricted to questions of science and technology, the Journal des Sçavans dealt with all the academic disciplines of the time, and thus had a wider readership than its English counterpart.

Preferential Ribosome Loading on the Stress-Upregulated mRNA Pool Shapes the Selective Translation under Stress Conditions

The reprogramming of gene expression is one of the key responses to environmental stimuli, whereas changes in mRNA do not necessarily bring forth corresponding changes of the protein, which seems partially due to the stress-induced selective translation. To address this issue, we systematically compared the transcriptome and translatome using self-produced and publicly available datasets to decipher how and to what extent the coordination and discordance between transcription and translation came to be in response to wounding (self-produced), dark to light transition, heat, hypoxia, Pi starvation and the pathogen-associated molecular pattern (elf18) in Arabidopsis. We found that changes in total mRNAs (transcriptome) and ribosome-protected fragments (translatome) are highly correlated upon dark to light transition or heat stress. However, this close correlation was generally lost under other four stresses analyzed in this study, especially during immune response, which suggests that transcription and translation are differentially coordinated under distinct stress conditions. Moreover, Gene Ontology (GO) enrichment analysis showed that typical stress responsive genes were upregulated at both transcriptional and translational levels, while non-stress-specific responsive genes were changed solely at either level or downregulated at both levels. Taking wounding responsive genes for example, typical stress responsive genes are generally involved in functional categories related to dealing with the deleterious effects caused by the imposed wounding stress, such as response to wounding, response to water deprivation and response to jasmonic acid, whereas non-stress-specific responsive genes are often enriched in functional categories like S-glycoside biosynthetic process, photosynthesis and DNA-templated transcription. Collectively, our results revealed the differential as well as targeted coordination between transcriptome and translatome in response to diverse stresses, thus suggesting a potential model wherein preferential ribosome loading onto the stress-upregulated mRNA pool could be a pacing factor for selective translation.

KSR1- and ERK-dependent Translational Regulation of the Epithelial-to-Mesenchymal Transition

The epithelial-to-mesenchymal transition (EMT) is considered a transcriptional process that induces a switch in cells from a polarized state to a migratory phenotype. Here we show that KSR1 and ERK promote EMT through the preferential translation of Epithelial-Stromal Interaction 1 (EPSTI1), which is required to induce the switch from E-to N-cadherin and coordinate migratory and invasive behavior. EPSTI1 is overexpressed in human colorectal cancer (CRC) cells. Disruption of KSR1 or EPSTI1 significantly impairs cell migration and invasion in vitro, and reverses EMT, in part, by decreasing the expression of N-cadherin and the transcriptional repressors of E-cadherin expression, ZEB1 and Slug. In CRC cells lacking KSR1, ectopic EPSTI1 expression restored the E-to N-cadherin switch, migration, invasion, and anchorage-independent growth. KSR1-dependent induction of EMT via selective translation of mRNAs reveals its underappreciated role in remodeling the translational landscape of CRC cells to promote their migratory and invasive behavior.

Psychology of Worldviews (selective translation)

The paper presents an author’s translation of fragments of previously unpublished in Russian «Psychology of Worldviews» by the German philosopher Karl Jaspers. The excerpts have been chosen to illustrate the basic considerations of the philosopher and psychiatrist regarding the metaphor of the shell introduced to describe a rigid worldview standpoint that people take to obtain support and shelter from the vulnerability and the uncertainty of environment, while, at the same time, paying for the seeming stability and certainty with the loss of their vitality and intensity of experiencing their own life. As Jaspers highlights, the shell as antinomic in its nature, and the inner contradictions related to the antinomies are resolved at the psychological level of existence, when the shell is melted and moulded into a new form, rather than at the level of formal logic, involving the reason. The author also supplies the translation with some comments and his own considerations on the topic.

Eukaryotic translation initiation factors as promising targets in cancer therapy

The regulation of the translation of messenger RNA (mRNA) in eukaryotic cells is critical for gene expression, and occurs principally at the initiation phase which is mainly regulated by eukaryotic initiation factors (eIFs). eIFs are fundamental for the translation of mRNA and as such act as the primary targets of several signaling pathways to regulate gene expression. Mis-regulated mRNA expression is a common feature of tumorigenesis and the abnormal activity of eIF complexes triggered by upstream signaling pathways is detected in many tumors, leading to the selective translation of mRNA encoding proteins involved in tumorigenesis, metastasis, or resistance to anti-cancer drugs, and making eIFs a promising therapeutic target for various types of cancers. Here, we briefly outline our current understanding of the biology of eIFs, mainly focusing on the effects of several signaling pathways upon their functions and discuss their contributions to the initiation and progression of tumor growth. An overview of the progress in developing agents targeting the components of translation machinery for cancer treatment is also provided.