Condensation of Ded1p Promotes a Translational Switch from Housekeeping to Stress Protein Production

Iserman, Christiane; Altamirano, Christine Desroches; Jegers, Ceciel; Friedrich, Ulrike; Zarin, Taraneh; Fritsch, Anatol; Mittasch, Matthäus; Domingues, António Miguel de Jesus; Hersemann, Lena; Jahnel, Marcus; Richter, Doris; Guenther, Ulf-Peter; Hentze, Matthias W.; Moses, Alan M.; Hyman, Anthony; Krämer, Günter; Kreysing, Moritz; Franzmann, Titus M.; Alberti, Simon

doi:10.1016/j.cell.2020.04.009

Cited by 149 publications

(207 citation statements)

References 75 publications

Supporting

Mentioning

190

Contrasting

Order By: Relevance

“…Furthermore, Ded1p also plays a key role in near-cognate initiation codon recognition-when Ded1p activity is repressed or diminished, the scanning ribosome initiates at near-cognate initiation codons that are within the 5' leader and immediately upstream of the secondary structure [103]. A recent report has documented a role for Ded1p as a stress sensor that responds to environmental changes [104]. At elevated temperatures (>39 • C), Ded1p condenses/aggregates, an event that is associated with a repression in translation of mRNAs encoding housekeeping functions [104].…”

Section: Ddx3xmentioning

confidence: 99%

“…A recent report has documented a role for Ded1p as a stress sensor that responds to environmental changes [104]. At elevated temperatures (>39 • C), Ded1p condenses/aggregates, an event that is associated with a repression in translation of mRNAs encoding housekeeping functions [104]. A role for DDX3X and DDX3Y in mammalian translation is less clearly defined and necessitates further investigation.…”

Section: Ddx3xmentioning

confidence: 99%

See 1 more Smart Citation

General and Target-Specific DExD/H RNA Helicases in Eukaryotic Translation Initiation

Shen

Pelletier

2020

IJMS

View full text Add to dashboard Cite

DExD (DDX)- and DExH (DHX)-box RNA helicases, named after their Asp-Glu-x-Asp/His motifs, are integral to almost all RNA metabolic processes in eukaryotic cells. They play myriad roles in processes ranging from transcription and mRNA-protein complex remodeling, to RNA decay and translation. This last facet, translation, is an intricate process that involves DDX/DHX helicases and presents a regulatory node that is highly targetable. Studies aimed at better understanding this family of conserved proteins have revealed insights into their structures, catalytic mechanisms, and biological roles. They have also led to the development of chemical modulators that seek to exploit their essential roles in diseases. Herein, we review the most recent insights on several general and target-specific DDX/DHX helicases in eukaryotic translation initiation.

show abstract

Section: Ddx3xmentioning

confidence: 99%

Section: Ddx3xmentioning

confidence: 99%

General and Target-Specific DExD/H RNA Helicases in Eukaryotic Translation Initiation

Shen

Pelletier

2020

IJMS

View full text Add to dashboard Cite

show abstract

“…Hsp70 colocalizes with stress granules ( Cherkasov et al, 2013 ; Walters et al, 2015 ), and stress-granule dispersal depends on Hsp70 and other chaperones ( Cherkasov et al, 2013 ; Walters et al, 2015 ; Kroschwald et al, 2015 ; Kroschwald et al, 2018 ). Three individual protein components of stress granules, poly(A)-binding protein Pab1, poly(U)-binding protein Pub1, and the DEAD-box RNA helicase Ded1, condense by phase separation in vitro when exposed to heat in a pH-dependent manner ( Riback et al, 2017 ; Kroschwald et al, 2018 ; Iserman et al, 2020 ). Pab1 and Ded1 condense by phase separation which depends strongly on temperature and pH.…”

Section: Discussionmentioning

confidence: 99%

Transient intracellular acidification regulates the core transcriptional heat shock response

Triandafillou

Katanski

Dinner

et al. 2020

eLife

View full text Add to dashboard Cite

Heat shock induces a conserved transcriptional program regulated by heat shock factor 1 (Hsf1) in eukaryotic cells. Activation of this heat shock response is triggered by heat-induced misfolding of newly synthesized polypeptides, and so has been thought to depend on ongoing protein synthesis. Here, using the budding yeast Saccharomyces cerevisiae, we report the discovery that Hsf1 can be robustly activated when protein synthesis is inhibited, so long as cells undergo cytosolic acidification. Heat shock has long been known to cause transient intracellular acidification which, for reasons which have remained unclear, is associated with increased stress resistance in eukaryotes. We demonstrate that acidification is required for heat shock response induction in translationally inhibited cells, and specifically affects Hsf1 activation. Physiological heat-triggered acidification also increases population fitness and promotes cell cycle reentry following heat shock. Our results uncover a previously unknown adaptive dimension of the well-studied eukaryotic heat shock response.

show abstract

“…To test if elevated pI is sufficient to restore a targeting signal, we first constructed an N-terminal Cox15 IDR in which we "knocked out" sequence-distributed features that we predict to be important for specific IDR function. To make this synthetic Cox15 IDR, we simulated the evolution of the Cox15 N-terminal IDR under a model that randomly evolves intrinsically disordered regions while preserving position-specific variation in evolutionary rates, but includes no specific constraints on the sequence-distributed molecular features used to train FAIDR (as in (Iserman et al, 2020)) ( Figure 3B, bottom). We note that this simulated IDR is not a completely random or generic IDR; for example, the simulated IDR shares 4/5 of the N-terminal amino acids with the wildtype Cox15 IDR from which it "evolved" in silico ( Figure 3B).…”

Section: Molecular Features In the Cox15 Idr Predictably Affect Mitocmentioning

confidence: 99%

Identifying molecular features that are associated with biological function of intrinsically disordered protein regions

Zarin

Strome

Peng

et al. 2020

Preprint

Self Cite

View full text Add to dashboard Cite

Previously, we showed that intrinsically disordered regions in proteins (IDRs) contain multiple sequence-distributed molecular features that are conserved over evolution, despite little sequence similarity that can be detected in alignments (Zarin et al. 2019). Here, we aim to use these molecular features to make specific functional predictions for individual IDRs and identify the molecular features within them that are responsible for specific functions. We find that the predictable functions are diverse, identifying previously known associated molecular features, as well as features that were previously not known to be associated with these functions. We experimentally confirm that elevated isoelectric point and hydrophobicity, features that are positively associated with mitochondrial localization, are necessary for mitochondrial targeting function. Remarkably, increasing isoelectric point in a synthetic IDR restores weak mitochondrial targeting. We believe feature analysis represents a new systematic approach to understand how biological functions of IDRs are specified by their protein sequences.

show abstract

Condensation of Ded1p Promotes a Translational Switch from Housekeeping to Stress Protein Production

Cited by 149 publications

References 75 publications

General and Target-Specific DExD/H RNA Helicases in Eukaryotic Translation Initiation

General and Target-Specific DExD/H RNA Helicases in Eukaryotic Translation Initiation

Transient intracellular acidification regulates the core transcriptional heat shock response

Identifying molecular features that are associated with biological function of intrinsically disordered protein regions

Contact Info

Product

Resources

About