Autophagy under glucose starvation enhances protein translation initiation in response to re‐addition of glucose in C2C12 myotubes

Nakai, Norihiro; Kitai, Saki; Iida, Noriko; Inoue, Sachika; Higashida, Kazuhiko

doi:10.1002/2211-5463.12970

Cited by 9 publications

(5 citation statements)

References 33 publications

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“…Similar to the anisomycin treatment above, this response was also dependent on the integrity of the S domain peptide motifs within ZAKα ( Figure 1 c). As a control for starvation-associated mTOR inhibition, we probed the phosphorylation state of S6 kinase (p-S6K) [ 25 ]. The arginines within the RGRYXXR/K motifs are subject to methylation [ 26 ] (phosphosite.org (accessed on 16 March 2023)).…”

Section: Resultsmentioning

confidence: 99%

Computational and Functional Analysis of Structural Features in the ZAKα Kinase

Johansen

Snieckute

Vind

et al. 2023

Cells

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The kinase ZAKα acts as the proximal sensor of translational impairment and ribotoxic stress, which results in the activation of the MAP kinases p38 and JNK. Despite recent insights into the functions and binding partners of individual protein domains in ZAKα, the mechanisms by which ZAKα binds ribosomes and becomes activated have remained elusive. Here, we highlight a short, thrice-repeated, and positively charged peptide motif as critical for the ribotoxic stress-sensing function of the Sensor (S) domain of ZAKα. We use this insight to demonstrate that the mutation of the SAM domain uncouples ZAKα activity from ribosome binding. Finally, we use 3D structural comparison to identify and functionally characterize an additional folded domain in ZAKα with structural homology to YEATS domains. These insights allow us to formulate a model for ribosome-templated ZAKα activation based on the re-organization of interactions between modular protein domains. In sum, our work both advances our understanding of the protein domains and 3D architecture of the ZAKα kinase and furthers our understanding of how the ribotoxic stress response is activated.

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Section: Resultsmentioning

confidence: 99%

Computational and Functional Analysis of Structural Features in the ZAKα Kinase

Johansen

Snieckute

Vind

et al. 2023

Cells

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“…Previous studies have demonstrated autophagy events happening during glucose starvation in fission yeast. 62 These results suggest an activation of protease activity in the early stages of glucose starvation, possibly by the recognition of ubiquitinated substrates, which are then digested into peptides. 63 While earlier investigations also showed ubiquitination of ribosomal protein uS3 in budding yeast during rapid stress response, 64 additional analysis involving measurements of ubiquitination levels and enzymatic activity of the proteases could be done to validate our results in glucose starvation.…”

Section: Discussionmentioning

confidence: 88%

Functional Consequences of Shifting Transcript Boundaries in Glucose Starvation

Nguyen,

Mori,

Yasuda

et al. 2023

Molecular and Cellular Biology

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Glucose is a major source of carbon and essential for the survival of many organisms, ranging from yeast to human. A sudden 60-fold reduction of glucose in exponentially growing fission yeast induces transcriptome-wide changes in gene expression. This regulation is multilayered, and the boundaries of transcripts are known to vary, with functional consequences at the protein level. By combining direct RNA sequencing with 5'-CAGE and short-read sequencing, we accurately defined the 5'- and 3'-ends of transcripts that are both poly(A) tailed and 5'-capped in glucose starvation, followed by proteome analysis. Our results confirm previous experimentally validated loci with alternative isoforms and reveal several transcriptome-wide patterns. First, we show that sense-antisense gene pairs are more strongly anticorrelated when a time lag is taken into account. Second, we show that the glucose starvation response initially elicits a shortening of 3'-UTRs and poly(A) tails, followed by a shortening of the 5'-UTRs at later time points. These result in domain gains and losses in proteins involved in the stress response. Finally, the relatively poor overlap both between differentially expressed genes (DEGs), differential transcript usage events (DTUs), and differentially detected proteins (DDPs) highlight the need for further study on post-transcriptional regulation mechanisms in glucose starvation.

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“…However, the TPCA profile of ribosomal proteins at 48 th hours of glucose deprivation are highly similar to data collected from samples without glucose deprivation suggesting resumption of translational activities. Previous studies had revealed system-wide attenuation in protein translation under glucose deprivation 36,37 that occurred independent of mRNA abundance 38 . Thus, the disassembly of ribosomes could possibly contribute or arise from decreased protein translation, an energy-intensive process 39,40 which prerequisite in many cells is the availability of glucose 37 .…”

Section: Resultsmentioning

confidence: 99%

Improvedin situCharacterization of Proteome-wide Protein Complex Dynamics with Thermal Proximity Co-Aggregation

Sun

Zheng

Wang

et al. 2023

Preprint

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Vast majority of cellular activities are carried out by protein complexes that assembled dynamically in response to cellular needs and environmental cues. Disarrayed cellular activities could arise from dysregulated protein complexes leading to diseases and developmental defects. Large scale efforts had uncovered a large repertoire of functionally uncharacterized protein complexes which necessitate new strategies to delineate their roles in various cellular activities and diseases. Thermal proximity co-aggregation profiling could be readily deployed to simultaneously characterize the dynamics for hundreds to thousands of protein complexes in situ across different cellular conditions. Toward this goal, we had optimized the original method both experimentally and computationally. In this new iteration termed Slim-TPCA, fewer temperatures are used increases throughputs by over 3X, while coupled with new scoring metrics and statistical evaluation resulted in minimal compromise in coverage and the detection of more relevant protein complexes. Overall, less samples are needed, false positives from batch effects are minimized and statistical evaluation time is reduced by two orders of magnitude. We applied Slim-TPCA to profile state of protein complexes in K562 cells under different duration of glucose deprivation. More protein complexes are found dissociated based on TPCA signature in accordance with expected downregulation of most cellular activities. These complexes include 55S ribosome and various respiratory complexes in mitochondria revealing the utility of TPCA to study protein complexes in organelles. On other hand, protein complexes involved in protein transport and degradation are found increasingly associated revealing their involvement in metabolic reprogramming during glucose deprivation. In summary. Slim-TPCA is an efficient strategy for proteome-wide characterization of protein complexes. The various algorithmic improvement of Slim-TPCA is available as Python package at https://pypi.org/project/Slim-TPCA/

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Autophagy under glucose starvation enhances protein translation initiation in response to re‐addition of glucose in C2C12 myotubes

Cited by 9 publications

References 33 publications

Computational and Functional Analysis of Structural Features in the ZAKα Kinase

Computational and Functional Analysis of Structural Features in the ZAKα Kinase

Functional Consequences of Shifting Transcript Boundaries in Glucose Starvation

Improvedin situCharacterization of Proteome-wide Protein Complex Dynamics with Thermal Proximity Co-Aggregation

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