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Filament formation by the translation factor eIF2B regulates protein synthesis in starved cells.

ABSTRACT: Cells exposed to starvation have to adjust their metabolism to conserve energy and protect themselves. Protein synthesis is one of the major energy-consuming processes and as such has to be tightly controlled. Many mechanistic details about how starved cells regulate the process of protein synthesis are still unknown. Here, we report that the essential translation initiation factor eIF2B forms filaments in starved budding yeast cells. We demonstrate that filamentation is triggered by starvation-induced acidification of the cytosol, which is caused by an influx of protons from the extracellular environment. We show that filament assembly by eIF2B is necessary for rapid and efficient downregulation of translation. Importantly, this mechanism does not require the kinase Gcn2. Furthermore, analysis of site-specific variants suggests that eIF2B assembly results in enzymatically inactive filaments that promote stress survival and fast recovery of cells from starvation. We propose that translation regulation through filament assembly is an efficient mechanism that allows yeast cells to adapt to fluctuating environments.

SUBMITTER: Nuske E

PROVIDER: S-EPMC7358136 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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Filament formation by the translation factor eIF2B regulates protein synthesis in starved cells.

Nüske Elisabeth E Marini Guendalina G Richter Doris D Leng Weihua W Bogdanova Aliona A Franzmann Titus M TM Pigino Gaia G Alberti Simon S

Biology open 20200708 7

Cells exposed to starvation have to adjust their metabolism to conserve energy and protect themselves. Protein synthesis is one of the major energy-consuming processes and as such has to be tightly controlled. Many mechanistic details about how starved cells regulate the process of protein synthesis are still unknown. Here, we report that the essential translation initiation factor eIF2B forms filaments in starved budding yeast cells. We demonstrate that filamentation is triggered by starvation- ...[more]

PMID: 32554487

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Project description:Iron is essential for growth and development of Chlamydia. Its long-term starvation in cultured mammalian cells leads to production of aberrant noninfectious chlamydial forms, also known as persistence. Immediate transcriptional responses to iron limitation have not been characterized, leaving a knowledge gap of how Chlamydia regulates its response to changes in iron availability. We used the fast-chelating agent 2,2'-bipyridyl (BPDL) to homogeneously starve Chlamydia trachomatis serovar L2 of iron, starting at 6 or 12 h postinfection. Immediate transcriptional responses were monitored after only 3 or 6 h of BPDL treatment, well before formation of aberrant Chlamydia. The first genomewide transcriptional response of C. trachomatis to iron starvation was subsequently determined utilizing RNA sequencing. Only 7% and 8% of the genome were differentially expressed in response to iron starvation at the early and middle stages of development, respectively. Biological pathway analysis revealed an overarching theme. Synthesis of macromolecular precursors (deoxynucleotides, amino acids, charged tRNAs, and acetyl coenzyme A [acetyl-CoA]) was upregulated, while energy-expensive processes (ABC transport and translation) were downregulated. A large fraction of differentially downregulated genes are involved in translation, including those encoding ribosome assembly and initiation and termination factors, which could be analogous to the translation downregulation triggered by stress in other prokaryotes during stringent responses. Additionally, transcriptional upregulation of DNA repair, oxidative stress, and tryptophan salvage genes reveals a possible coordination of responses to multiple antimicrobial and immunological insults. These responses of replicative-phase Chlamydia to iron starvation indicate a prioritization of survival over replication, enabling the pathogen to "stock the pantry" with ingredients needed for rapid growth once optimal iron levels are restored. IMPORTANCE By utilizing an experimental approach that monitors the immediate global response of Chlamydia trachomatis to iron starvation, clues to long-standing issues in Chlamydia biology are revealed, including how Chlamydia adapts to this stress. We determined that this pathogen initiates a transcriptional program that prioritizes replenishment of nutrient stores over replication, possibly in preparation for rapid growth once optimal iron levels are restored. Transcription of genes for biosynthesis of metabolic precursors was generally upregulated, while those involved in multiple steps of translation were downregulated. We also observed an increase in transcription of genes involved in DNA repair and neutralizing oxidative stress, indicating that Chlamydia employs an "all-or-nothing" strategy. Its small genome limits its ability to tailor a specific response to a particular stress. Therefore, the "all-or-nothing" strategy may be the most efficient way of surviving within the host, where the pathogen likely encounters multiple simultaneous immunological and nutritional insults.

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Filament formation by the translation factor eIF2B regulates protein synthesis in starved cells.

Publications

Filament formation by the translation factor eIF2B regulates protein synthesis in starved cells.

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