brain fingerprinting blotted science tab

However, under chronic metabolic limitations, little is known of whether the transcriptome has a hierarchically defined translational design, which could arise to preserve the anabolic capacity of the cell. To this end, higher eukaryotes have evolved an arsenal of mechanisms to selectively translate stress mRNAs in response to sudden changes ( 8– 14).

The intrinsic plasticity of the translatome has been observed in a number of biological circumstances to rapidly respond to cellular perturbations. This poses the question of whether the transcriptome has an innate translational hierarchy that serves to prioritize basic cellular biosynthetic routes under critical metabolic constraints. To reestablish the anabolic demand required to awaken from a low metabolic state, cells must preserve the ability to quickly generate new ribosomes and reconstitute the protein synthetic capacity, a process that, in higher metazoans, is largely controlled at the translational level ( 6, 7). A reduction in the number of available ribosomes, along with the protein synthetic capacity, alters the repertoire of cellular transcripts engaged in translation, modifying the translational program of the cell. Many inhibitory growth stimuli are characterized by an overall reduction of mTOR signaling, and, more recently, it was observed that prolonged mTOR inhibition triggers the selective degradation of cellular ribosomes, in a process termed ribophagy ( 5). Upon nutritional limitations, mTOR acts as a metabolic switch to lower global metabolism. This circuitry is central for the cell to adapt to acute changes in extracellular or intracellular conditions or to differentiate the metabolic needs of specific cell types in distinct tissues and organs ( 4). To a large extent, the tight communication among sensors and effectors is mediated by the mammalian target of rapamycin (mTOR) kinase, which acts to coordinate the overall metabolic balance in the cell ( 3). To maintain cellular homeostasis, the rate of protein synthesis is dynamically controlled by specific factors that sense external and internal cues, including nutrient availability, oxygen accessibility, and energetic status, all acting to determine the equilibrium between anabolic and catabolic cellular processes ( 2). Ribosomes play a key role in this process based on their ability to synthesize new proteins, and an increase in their numbers is critical to undergo cell replication ( 1). The production of cellular mass is a prerequisite for cell replication as it endows the daughter cells with molecular machineries essential to execute the inherited genetic information. Characterizing the LARP1-protected translatome revealed a set of 5′TOP transcript isoforms other than RPs involved in energy production and in mitochondrial function, among other processes, indicating that the mTOR-LARP1-5′TOP axis acts at the translational level as a primary guardian of the cellular anabolic capacity. Here, we show that under critical metabolic constraints characterized by mTOR inhibition, LARP1 complexed with the 40 S subunit protects from ribophagy the mRNAs regulon for ribosome biogenesis and protein synthesis, acutely preparing the translatome to promptly resume ribosomes production after growth conditions return permissive. As ribosome synthesis depends on RP mRNA translation, a priority within the translatome architecture should exist to ensure the preservation of ribosome biogenesis capacity, particularly under adverse growth conditions.

Critical to sustain nearly all cellular activities, ribosome biogenesis requires the translation of ~200 factors of which 80 are ribosomal proteins (RPs). Ribosomes execute the transcriptional program in every cell.

Brain fingerprinting blotted science tab