Evolutionary conserved role of eukaryotic translation factor eIF5A in the regulation of actin-nucleating formins

AbstractElongation factor eIF5A is required for the translation of consecutive prolines, and was shown in yeast to translate polyproline-containing Bni1, an actin-nucleating formin required for polarized growth during mating. Here we show that Drosophila eIF5A can functionally replace yeast eIF5A and is required for actin-rich cable assembly during embryonic dorsal closure (DC). Furthermore, Diaphanous, the formin involved in actin dynamics during DC, is regulated by and mediates eIF5A effects. Finally, eIF5A controls cell migration and regulates Diaphanous levels also in mammalian cells. Our results uncover an evolutionary conserved role of eIF5A regulating cytoskeleton-dependent processes…

Fertility and Polarized Cell Growth Depends on eIF5A for Translation of Polyproline-Rich Formins in Saccharomyces cerevisiae

eIF5A is an essential and evolutionary conserved translation elongation factor, which has recently been proposed to be required for the translation of proteins with consecutive prolines. The binding of eIF5A to ribosomes occurs upon its activation by hypusination, a modification that requires spermidine, an essential factor for mammalian fertility that also promotes yeast mating. We show that in response to pheromone, hypusinated eIF5A is required for shmoo formation, localization of polarisome components, induction of cell fusion proteins, and actin assembly in yeast. We also show that eIF5A is required for the translation of Bni1, a proline-rich formin involved in polarized growth during …

Cross-regional view of functional and taxonomic microbiota composition in obesity and post-obesity treatment shows country specific microbial contribution

This work was supported by CONICYT-Chile through the FONDECYT [n° 3160525] (DM) and by Universidad San Sebastián, and by grants to AM from the Spanish Ministry of Economy and Competitiveness (projects SAF2012-31187, SAF2013-49788-EXP, SAF2015-65878-R), Carlos III Health Institute (Projects PIE14/00045 and AC15/00022), Generalitat Valenciana (Project PrometeoII/2014/065 and Prometeo/2018/A/133), Asociación Española Contra el Cancer (Project AECC 2017-1485) and co-financed by the European Regional Development Fund (ERDF).

Modulation of protein synthesis and degradation maintains proteostasis during yeast growth at different temperatures

To understand how cells regulate each step in the flow of gene expression is one of the most fundamental goals in molecular biology. In this work, we have investigated several protein turnover-related steps in the context of gene expression regulation in response to changes in external temperature in model yeast Saccharomyces cerevisiae. We have found that the regulation of protein homeostasis is stricter than mRNA homeostasis. Although global translation and protein degradation rates are found to increase with temperature, the increase of the catalytic activity of ribosomes is higher than the global translation rate suggesting that yeast cells adapt the amount of translational machinery to…

Msb2 is a Ste11 membrane concentrator required for full activation of the HOG pathway.

The high osmolarity glycerol (HOG) pathway, composed of membrane-associated osmosensors, adaptor proteins and core signaling kinases, is essential for the survival of yeast cells under hyper-osmotic stress. Here, we studied how the MAPKKK Ste11 might change its protein interaction profile during acute stress exposure, with an emphasis on the sensory system of the so-called Sho1/Msb2 signaling branch. To characterize the transience of protein-protein interactions we utilized a recently described enzymatic in vivo protein proximity assay (M-track). Accordingly, interaction signals between Ste11 and many of its signaling partners can already be detected even under basal conditions. In most cas…

The mRNA cap-binding protein Cbc1 is required for high and timely expression of genes by promoting the accumulation of gene-specific activators at promoters

The highly conserved Saccharomyces cerevisiae cap-binding protein Cbc1/Sto1 binds mRNA co-transcriptionally and acts as a key coordinator of mRNA fate. Recently, Cbc1 has also been implicated in transcription elongation and pre-initiation complex (PIC) formation. Previously, we described Cbc1 to be required for cell growth under osmotic stress and to mediate osmostress-induced translation reprogramming. Here, we observe delayed global transcription kinetics in cbc1Δ during osmotic stress that correlates with delayed recruitment of TBP and RNA polymerase II to osmo-induced promoters. Interestingly, we detect an interaction between Cbc1 and the MAPK Hog1, which controls most gene expression c…

Inflammatory cytokines shape a changing DNA methylome in monocytes mirroring disease activity in rheumatoid arthritis

Objective: Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease that mainly targets joints. Monocytes and macrophages are critical in RA pathogenesis and contribute to inflammatory lesions. These extremely plastic cells respond to extracellular signals which cause epigenomic changes that define their pathogenic phenotype. Here, we interrogated how DNA methylation alterations in RA monocytes are determined by extracellular signals. Methods: High-throughput DNA methylation analyses of patients with RA and controls and in vitro cytokine stimulation were used to investigate the underlying mechanisms behind DNA methylation alterations in RA as well as their relationship with clinic…

Cellular response to external signals in S. cerevisiae

En esta tesis, se utilizó como organismo modelo la levadura Saccharomyces cerevisiae para obtener conocimiento fundamental sobre una variedad de mecanismos moleculares utilizados por la célula para responder y adaptarse a los estímulos externos. En respuesta al aumento de la osmolaridad externa, la ruta de señalización MAPK High Osmolarity Glycerol (HOG) se activa para mediar cambios en diversas funciones celulares, incluyendo la reprogramación global de la transcripción y traducción, con el fin último de lograr la adaptación. Tras la detección de alta osmolaridad externa, la señal se transduce a través de dos ramas funcionalmente redundantes pero mecanísticamente distintas, SLN1 y SHO1, pa…

Corrigendum to “External conditions inversely change the RNA polymerase II elongation rate and density in yeast” [Biochim. Biophys. Acta 1829/11 (2013) 1248–1255]

External conditions inversely change the RNA polymerase II elongation rate and density in yeast.

Elongation speed is a key parameter in RNA polymerase II (RNA pol II) activity. It affects the transcription rate, while it is conditioned by the physicochemical environment it works in at the same time. For instance, it is well-known that temperature affects the biochemical reactions rates. Therefore in free-living organisms that are able to grow at various environmental temperatures, such as the yeast Saccharomyces cerevisiae, evolution should have not only shaped the structural and functional properties of this key enzyme, but should have also provided mechanisms and pathways to adapt its activity to the optimal performance required. We studied the changes in RNA pol II elongation speed …