title: Ribosomal stress activates eEF2K-eEF2 pathway causing translation elongation inhibition and recruitment of terminal oligopyrimidine (TOP) mRNAs on polysomes.
abstract: The synthesis of adequate amounts of ribosomes is an essential task for the cell. It is therefore not surprising that regulatory circuits exist to organize the synthesis of ribosomal components. It has been shown that defect in ribosome biogenesis (ribosomal stress) induces apoptosis or cell cycle arrest through activation of the tumor suppressor p53. This mechanism is thought to be implicated in the pathophysiology of a group of genetic diseases such as Diamond Blackfan Anemia which are called ribosomopathies. We have identified an additional response to ribosomal stress that includes the activation of eukaryotic translation elongation factor 2 kinase with a consequent inhibition of translation elongation. This leads to a translational reprogramming in the cell that involves the structurally defined group of messengers called terminal oligopyrimidine (TOP) mRNAs which encode ribosomal proteins and translation factors. In fact, while general protein synthesis is decreased by the impairment of elongation, TOP mRNAs are recruited on polysomes causing a relative increase in the synthesis of TOP mRNA-encoded proteins compared to other proteins. Therefore, in response to ribosomal stress, there is a change in the translation pattern of the cell which may help restore a sufficient level of ribosomes.
authors.affiliation: Department of Biology, University Tor Vergata, Roma, 00133, Italy.
authors.forename: Angelo
authors.initials: A
authors.lastname: Gismondi
authors.affiliation: Department of Biology, University Tor Vergata, Roma, 00133, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Caldarola
authors.affiliation: Department of Biology, University Tor Vergata, Roma, 00133, Italy.
authors.forename: Gaia
authors.initials: G
authors.lastname: Lisi
authors.affiliation: Department of Biology, University Tor Vergata, Roma, 00133, Italy.
authors.forename: Giada
authors.initials: G
authors.lastname: Juli
authors.affiliation: Department of Biology, University Tor Vergata, Roma, 00133, Italy.
authors.forename: Lidia
authors.initials: L
authors.lastname: Chellini
authors.affiliation: Centre for Biological Sciences, University of Southampton, Southampton, UK.
authors.forename: Valentina
authors.initials: V
authors.lastname: Iadevaia
authors.affiliation: Centre for Biological Sciences, University of Southampton, Southampton, UK.
authors.forename: Christopher G
authors.initials: CG
authors.lastname: Proud
authors.affiliation: Department of Biology, University Tor Vergata, Roma, 00133, Italy loreni@uniroma2.it.
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Loreni
mesh_terms: D045744:Cell Line, Tumor; D054736:Elongation Factor 2 Kinase / Q000378:metabolism*; D015977:Eukaryotic Initiation Factor-1 / Q000096:biosynthesis / Q000235:genetics; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes / Q000378:metabolism; D010441:Peptide Chain Elongation, Translational / Q000187:drug effects; D020652:Peptide Elongation Factor 2 / Q000378:metabolism*; D011132:Polyribosomes / Q000378:metabolism*; D038641:RNA 5' Terminal Oligopyrimidine Sequence; D012333:RNA, Messenger / Q000378:metabolism*; D012269:Ribosomal Proteins / Q000037:antagonists & inhibitors; D012270:Ribosomes / Q000502:physiology; D013312:Stress, Physiological / Q000235:genetics*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D015977:Eukaryotic Initiation Factor-1; D046912:Multiprotein Complexes; D020652:Peptide Elongation Factor 2; D012333:RNA, Messenger; D012269:Ribosomal Proteins; C026022:eukaryotic peptide initiation factor-1A; C517689:EEF2K protein, human; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D054736:Elongation Factor 2 Kinase; D048049:Extracellular Signal-Regulated MAP Kinases