scholarly journals Are stress granules the RNA analogs of misfolded protein aggregates?

RNA ◽  
2021 ◽  
pp. rna.079000.121
Author(s):  
Nina Ripin ◽  
Roy Parker
Keyword(s):  
Protein Aggregates ◽  
Eukaryotic Cells ◽  
Misfolded Protein ◽  
Granule Formation ◽  
Unfolded Protein ◽  
Rna Chaperones ◽  
Rnp Granules ◽  
Disease Understanding ◽  
Insight Into

RNP granules are ubiquitous features of eukaryotic cells. Several observations argue that the formation of at least some RNP granules can be considered analogous to the formation of unfolded protein aggregates. First, unfolded protein aggregates form from the exposure of promiscuous protein interaction surfaces, while some mRNP granules form, at least in part, by promiscuous intermolecular RNA-RNA interactions due to exposed RNA surfaces when mRNAs are not engaged with ribosomes. Second, analogous to the role of protein chaperones in preventing misfolded protein aggregation, cells contain abundant “RNA chaperones” to limit inappropriate RNA-RNA interactions and prevent mRNP granule formation. Third, analogous to the role of protein aggregates in diseases, situations where RNA aggregation exceeds the capacity of RNA chaperones to disaggregate RNAs may contribute to human disease. Understanding that RNP granules can be considered as promiscuous, reversible RNA aggregation events allows insight into their composition and how cells have evolved functions for RNP granules.

Role of the Saccharomyces cerevisiae Rad9 protein in sensing and responding to DNA damage

2003 ◽  
Vol 31 (1) ◽  
pp. 242-246 ◽  
Author(s):  
G.W.-L. Toh ◽  
N.F. Lowndes
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Dna Damage ◽  
Cellular Responses ◽  
Eukaryotic Cells ◽  
Genome Damage ◽  
Dna Damage Checkpoints ◽  
Repair Mechanisms ◽  
Sense And Respond ◽  
Insight Into

Eukaryotic cells have evolved surveillance mechanisms, known as DNA-damage checkpoints, that sense and respond to genome damage. DNA-damage checkpoint pathways ensure co-ordinated cellular responses to DNA damage, including cell cycle delays and activation of repair mechanisms. RAD9, from Saccharomyces cerevisiae, was the first damage checkpoint gene to be identified, although its biochemical function remained unknown until recently. This review examines briefly work that provides significant insight into how Rad9 activates the checkpoint signalling kinase Rad53.

scholarly journals Endoplasmic reticulum turnover: ER-phagy and other flavors in selective and non-selective ER clearance

F1000Research ◽  
2018 ◽  
Vol 7 ◽  
pp. 454 ◽  
Author(s):  
Ilaria Fregno ◽  
Maurizio Molinari
Keyword(s):  
Endoplasmic Reticulum ◽  
Protein Biosynthesis ◽  
Misfolded Proteins ◽  
Eukaryotic Cells ◽  
Unfolded Protein ◽  
Calcium Storage ◽  
Live Bacteria ◽  
And Function ◽  
Developmental Conditions

The endoplasmic reticulum (ER) is a highly dynamic organelle in eukaryotic cells. It is deputed to lipid and protein biosynthesis, calcium storage, and the detoxification of various exogenous and endogenous harmful compounds. ER activity and size must be adapted rapidly to environmental and developmental conditions or biosynthetic demand. This is achieved on induction of thoroughly studied transcriptional/translational programs defined as “unfolded protein responses” that increase the ER volume and the expression of ER-resident proteins regulating the numerous ER functions. Less understood are the lysosomal catabolic processes that maintain ER size at steady state, that prevent excessive ER expansion during ER stresses, or that ensure return to physiologic ER size during recovery from ER stresses. These catabolic processes may also be activated to remove ER subdomains where proteasome-resistant misfolded proteins or damaged lipids have been segregated. Insights into these catabolic mechanisms have only recently emerged with the identification of so-called ER-phagy receptors, which label specific ER subdomains for selective lysosomal delivery for clearance. Here, in eight chapters and one addendum, we comment on recent advances in ER turnover pathways induced by ER stress, nutrient deprivation, misfolded proteins, and live bacteria. We highlight the role of yeast (Atg39 and Atg40) and mammalian (FAM134B, SEC62, RTN3, and CCPG1) ER-phagy receptors and of autophagy genes in selective and non-selective catabolic processes that regulate cellular proteostasis by controlling ER size, turnover, and function.

scholarly journals Mitochondrial fission facilitates the selective mitophagy of protein aggregates

2017 ◽  
Vol 216 (10) ◽  
pp. 3231-3247 ◽  
Author(s):  
Jonathon L. Burman ◽  
Sarah Pickles ◽  
Chunxin Wang ◽  
Shiori Sekine ◽  
Jose Norberto S. Vargas ◽  
...  
Keyword(s):  
Protein Aggregation ◽  
Matrix Protein ◽  
Mitochondrial Fission ◽  
Protein Aggregates ◽  
Mitochondrial Matrix ◽  
Unfolded Protein ◽  
Protein Response ◽  
Mitochondrial Networks ◽  
Mitochondrial Unfolded Protein Response

Within the mitochondrial matrix, protein aggregation activates the mitochondrial unfolded protein response and PINK1–Parkin-mediated mitophagy to mitigate proteotoxicity. We explore how autophagy eliminates protein aggregates from within mitochondria and the role of mitochondrial fission in mitophagy. We show that PINK1 recruits Parkin onto mitochondrial subdomains after actinonin-induced mitochondrial proteotoxicity and that PINK1 recruits Parkin proximal to focal misfolded aggregates of the mitochondrial-localized mutant ornithine transcarbamylase (ΔOTC). Parkin colocalizes on polarized mitochondria harboring misfolded proteins in foci with ubiquitin, optineurin, and LC3. Although inhibiting Drp1-mediated mitochondrial fission suppresses the segregation of mitochondrial subdomains containing ΔOTC, it does not decrease the rate of ΔOTC clearance. Instead, loss of Drp1 enhances the recruitment of Parkin to fused mitochondrial networks and the rate of mitophagy as well as decreases the selectivity for ΔOTC during mitophagy. These results are consistent with a new model that, instead of promoting mitophagy, fission protects healthy mitochondrial domains from elimination by unchecked PINK1–Parkin activity.

scholarly journals Selective Autophagy by Close Encounters of the Ubiquitin Kind

Cells ◽  
2020 ◽  
Vol 9 (11) ◽  
pp. 2349 ◽  
Author(s):  
Anna Vainshtein ◽  
Paolo Grumati
Keyword(s):  
Protein Aggregates ◽  
Degradation Process ◽  
Eukaryotic Cells ◽  
Post Translational Modifications ◽  
Selective Autophagy ◽  
Close Encounters ◽  
Ubiquitin Binding ◽  
Ubiquitin Binding Domain ◽  
Cellular Turnover

Autophagy, a bulk degradation process within eukaryotic cells, is responsible for cellular turnover and nutrient liberation during starvation. Increasing evidence indicate that this process can be extremely discerning. Selective autophagy segregates and eliminates protein aggregates, damaged organelles, and invading organisms. The specificity of this process is largely mediated by post-translational modifications (PTMs), which are recognized by autophagy receptors. These receptors grant autophagy surgical precision in cargo selection, where only tagged substrates are engulfed within autophagosomes and delivered to the lysosome for proteolytic breakdown. A growing number of selective autophagy receptors have emerged including p62, NBR1, OPTN, NDP52, TAX1BP1, TOLLIP, and more continue to be uncovered. The most well-documented PTM is ubiquitination and selective autophagy receptors are equipped with a ubiquitin binding domain and an LC3 interacting region which allows them to physically bridge cargo to autophagosomes. Here, we review the role of ubiquitin and ubiquitin-like post-translational modifications in various types of selective autophagy.

scholarly journals Reversion of protein aggregation mediated by Sso7d in cell extracts of Sulfolobus solfataricus

2004 ◽  
Vol 381 (1) ◽  
pp. 249-255 ◽  
Author(s):  
Annamaria GUAGLIARDI ◽  
Lucia MANCUSI ◽  
Mosè ROSSI
Keyword(s):  
Escherichia Coli ◽  
Protein Aggregation ◽  
Atp Hydrolysis ◽  
Sulfolobus Solfataricus ◽  
Protein Aggregates ◽  
Eukaryotic Cells ◽  
Cell Extracts ◽  
Thermophilic Archaeon

In eukaryotic cells and in Escherichia coli, reversion of protein aggregation is mediated by the network of chaperones belonging to Hsp70 and Hsp100 families [Weibezahn, Bukau and Mogk (2004) Microb. Cell Fact. 3, 1–12]. The thermophilic prokaryotes of the archaea domain lack homologues of these chaperone families, and the mechanisms they use to rescue aggregated proteins are unknown [Macario, Malz and Conway de Macario (2004) Front. Biosci. 9, 1318–1332]. In the present study, we show that stable protein aggregates can be detected in extracts of starved cells of the thermophilic archaeon Sulfolobus solfataricus, and that the protein Sso7d interacts with the aggregates and mediates the disassembly of the aggregates and the re-activation of insolubilized β-glycosidase in the presence of ATP hydrolysis. Furthermore, we report that heat-induced protein aggregates in extracts of exponential cells of S. solfataricus contain Sso7d that rescues insolubilized proteins in the presence of ATP hydrolysis. Results of these experiments performed in cell extracts are consistent with an in vivo role of Sso7d in reverting protein aggregation.

scholarly journals New Insight into the Role of the PhaP Phasin of Ralstonia eutropha in Promoting Synthesis of Polyhydroxybutyrate

2001 ◽  
Vol 183 (7) ◽  
pp. 2394-2397 ◽  
Author(s):  
Gregory M. York ◽  
JoAnne Stubbe ◽  
Anthony J. Sinskey
Keyword(s):  
Ralstonia Eutropha ◽  
Volume Ratio ◽  
Growth Conditions ◽  
Deletion Strain ◽  
Granule Formation ◽  
Phb Production ◽  
Polyhydroxyalkanoate Synthase ◽  
Low Levels ◽  
Insight Into

ABSTRACT Phasins are proteins that are proposed to play important roles in polyhydroxyalkanoate synthesis and granule formation. Here the phasin PhaP of Ralstonia eutropha has been analyzed with regard to its role in the synthesis of polyhydroxybutyrate (PHB). Purified recombinant PhaP, antibodies against PhaP, and an R. eutropha phaP deletion strain have been generated for this analysis. Studies with the phaP deletion strain show that PhaP must accumulate to high levels in order to play its normal role in PHB synthesis and that the accumulation of PhaP to low levels is functionally equivalent to the absence of PhaP. PhaP positively affects PHB synthesis under growth conditions which promote production of PHB to low, intermediate, or high levels. The levels of PhaP generally parallel levels of PHB in cells. The results are consistent with models whereby PhaP promotes PHB synthesis by regulating the surface/volume ratio of PHB granules or by interacting with polyhydroxyalkanoate synthase and indicate that PhaP plays an important role in PHB synthesis from the early stages in PHB production and across a range of growth conditions.

scholarly journals The Transcriptional Response to Oxidative Stress is Independent of Stress-Granule Formation

2022 ◽  
Author(s):  
Amanjot Singh ◽  
Arvind Reddy Kandi ◽  
Deepa Jayaprakashappa ◽  
Guillaume Thuery ◽  
Devam J Purohit ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Stress Responses ◽  
Transcriptional Response ◽  
Granule Formation ◽  
Unfolded Protein ◽  
Transcriptional Changes ◽  
Translational Arrest ◽  
Shock Proteins ◽  
Gene Expression Alterations

Cells respond to stress with translational arrest, robust transcriptional changes, and transcription-independent formation of mRNP assemblies termed stress granules (SGs). Despite considerable interest in the role of SGs in oxidative, unfolded-protein and viral stress responses, whether and how SGs contribute to stress-induced transcription has not been rigorously examined. To address this, we characterized transcriptional changes in Drosophila S2 cells induced by acute oxidative-stress and assessed how these were altered under conditions that disrupted SG assembly. Oxidative stress for 3-hours predominantly resulted in induction or upregulation of stress-responsive mRNAs whose levels peaked during recovery after stress cessation. The stress-transcriptome is enriched in mRNAs coding for chaperones, including HSP70s, small heat shock proteins, glutathione transferases, and several non-coding RNAs. Oxidative stress also induced cytoplasmic SGs that disassembled 3-hours after stress cessation. As expected, RNAi-mediated knockdown of the conserved G3BP1/Rasputin protein inhibited SG assembly. However, this disruption had no significant effect on the stress-induced transcriptional response or stress-induced translational arrest. Thus, SG assembly and stress-induced gene expression alterations appear to be driven by distinctive signaling processes. We suggest that while SG assembly represents a fast, transient mechanism, the transcriptional response enables a slower, longer-lasting mechanism for adaptation to and recovery from cell stress.

scholarly journals Promiscuous interactions and protein disaggregases determine the material state of stress-inducible RNP granules

eLife ◽  
2015 ◽  
Vol 4 ◽  
Author(s):  
Sonja Kroschwald ◽  
Shovamayee Maharana ◽  
Daniel Mateju ◽  
Liliana Malinovska ◽  
Elisabeth Nüske ◽  
...  
Keyword(s):  
Mammalian Cells ◽  
Extreme Environments ◽  
Stress Granules ◽  
Protein Aggregates ◽  
Living Cells ◽  
Granule Formation ◽  
P Bodies ◽  
State Of Stress ◽  
Material State ◽  
Rnp Granules

RNA-protein (RNP) granules have been proposed to assemble by forming solid RNA/protein aggregates or through phase separation into a liquid RNA/protein phase. Which model describes RNP granules in living cells is still unclear. In this study, we analyze P bodies in budding yeast and find that they have liquid-like properties. Surprisingly, yeast stress granules adopt a different material state, which is reminiscent of solid protein aggregates and controlled by protein disaggregases. By using an assay to ectopically nucleate RNP granules, we further establish that RNP granule formation does not depend on amyloid-like aggregation but rather involves many promiscuous interactions. Finally, we show that stress granules have different properties in mammalian cells, where they show liquid-like behavior. Thus, we propose that the material state of RNP granules is flexible and that the solid state of yeast stress granules is an adaptation to extreme environments, made possible by the presence of a powerful disaggregation machine.

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