Translational quality control and reprogramming during stress adaptation

Han, Nien-Ching; Kelly, Paul; Ibba, Michael

doi:10.1016/j.yexcr.2020.112161

Cited by 16 publications

(15 citation statements)

References 137 publications

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“…Interestingly, numerous stress responses impact on translation factors, such as eIF4F and eIF2, that regulate mRNA translation at initiation or elongation steps. Suppression of global protein synthesis is generally paralleled by the selective translation of mRNAs encoding specific proteins that are crucial for cellular restoration and survival [ 19 , 20 ]. Recent genome-wide ribosome profiling studies have demonstrated proteome complexity, alternative translation initiation and ribosome pausing during elongation, which are all manifestations of stress-induced translational reprogramming [ 21–23 ].…”

Section: Stress Response Pathways Connected With Translation Reprogra...mentioning

confidence: 99%

A comprehensive coverage insurance for cells: revealing links between ribosome collisions, stress responses and mRNA surveillance

Mühlemann

2022

RNA Biology

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Cells of metazoans respond to internal and external stressors by activating stress response pathways that aim for re-establishing cellular homoeostasis or, if this cannot be achieved, triggering programmed cell death. Problems during translation, arising from defective mRNAs, tRNAs, ribosomes or protein misfolding, can activate stress response pathways as well as mRNA surveillance and ribosome quality control programs. Recently, ribosome collisions have emerged as a central signal for translational stress and shown to elicit different stress responses. Here, we review our current knowledge about the intricate mutual connections between ribosome collisions, stress response pathways and mRNA surveillance. A central factor connecting the sensing of collided ribosomes with degradation of the nascent polypeptides, dissociation of the stalled ribosomes and degradation of the mRNA by no-go or non-stop decay is the E3-ligase ZNF598. We tested whether ZNF598 also plays a role in nonsense-mediated mRNA decay (NMD) but found that it is dispensable for this translation termination-associated mRNA surveillance pathway, which in combination with other recent data argues against stable ribosome stalling at termination codons being the NMD-triggering signal.

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Section: Stress Response Pathways Connected With Translation Reprogra...mentioning

confidence: 99%

A comprehensive coverage insurance for cells: revealing links between ribosome collisions, stress responses and mRNA surveillance

Mühlemann

2022

RNA Biology

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“…Eukaryotic protein levels are predominantly controlled by mRNA translation ( 1 ), an energetically expensive process ( 2 ) that is highly regulated ( 3 ) to ensure optimal transit times for protein quality control ( 4 ) and to fashion the cellular response to environmental stress and changes in the availability of energy and/or nutrients ( 5 ). A primary driver of this regulation is the specific phosphorylation (on Thr 56 ) of the guanosine triphosphate (GTP)–dependent translocase, eukaryotic elongation factor 2 (eEF-2).…”

Section: Introductionmentioning

confidence: 99%

Structural basis for the calmodulin-mediated activation of eukaryotic elongation factor 2 kinase

et al. 2022

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Translation is a tightly regulated process that ensures optimal protein quality and enables adaptation to energy/nutrient availability. The α-kinase eukaryotic elongation factor 2 kinase (eEF-2K), a key regulator of translation, specifically phosphorylates the guanosine triphosphatase eEF-2, thereby reducing its affinity for the ribosome and suppressing the elongation phase of protein synthesis. eEF-2K activation requires calmodulin binding and autophosphorylation at the primary stimulatory site, T348. Biochemical studies predict a calmodulin-mediated activation mechanism for eEF-2K distinct from other calmodulin-dependent kinases. Here, we resolve the atomic details of this mechanism through a 2.3-Å crystal structure of the heterodimeric complex of calmodulin and the functional core of eEF-2K (eEF-2KTR). This structure, which represents the activated T348-phosphorylated state of eEF-2KTR, highlights an intimate association of the kinase with the calmodulin C-lobe, creating an “activation spine” that connects its amino-terminal calmodulin-targeting motif to its active site through a conserved regulatory element.

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“…Perturbations of translation via this pathway have been observed as a response to various stressors, including temperature, oxidative environment, and nutrient deprivation. 91,92 The strongest correlation between proteomic and metabolomic datasets occurred across two protein clusters and a single small molecule cluster. The cluster of metabolites was comprised of isolated amino acids and short polypeptides.…”

Section: Discussionmentioning

confidence: 99%

“…Perturbations of translation via this pathway have been observed as a response to various stressors, including temperature, oxidative environment, and nutrient deprivation. 91,92…”

Section: Discussionmentioning

confidence: 99%

Proteomic and metabolomic profiling of acute and chronic stress events associated with military exercises

et al. 2022

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Translational quality control and reprogramming during stress adaptation

Cited by 16 publications

References 137 publications

A comprehensive coverage insurance for cells: revealing links between ribosome collisions, stress responses and mRNA surveillance

A comprehensive coverage insurance for cells: revealing links between ribosome collisions, stress responses and mRNA surveillance

Structural basis for the calmodulin-mediated activation of eukaryotic elongation factor 2 kinase

Proteomic and metabolomic profiling of acute and chronic stress events associated with military exercises

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