scholarly journals P38 activation induces the dissociation of tristetraprolin from Argonaute 2 to increase ARE-mRNA stabilization

2018 ◽  
Vol 29 (8) ◽  
pp. 988-1002 ◽  
Author(s):  
Mei-Yan Qi ◽  
Jing-Wen Song ◽  
Zhuo Zhang ◽  
Shuang Huang ◽  
Qing Jing
Keyword(s):  
Mrna Stability ◽  
Mrna Decay ◽  
Mrna Degradation ◽  
Processing Bodies ◽  
Mrna Stabilization ◽  
Argonaute 2 ◽  
Core Member ◽  
Mrna Granules

Tristetraprolin (TTP) destabilizes AU-rich element (ARE)-containing mRNA by directly binding with their 3′UTR. P38 stimulation substantially increases ARE-mRNA stability, at least through repressing TTP. However, the mechanism by which P38 keeps TTP inactive has not been fully understood. TTP and ARE-mRNA localize to processing bodies (PBs), the mRNA granules associated with mRNA silencing. Here, we detected the influence of P38 on TTP localization within PBs and found that P38 regulates TTP localization within PBs. Through luciferase-based systems, we demonstrated that PBs depletion significantly increased ARE-mRNA stability inhibited by TTP. Additionally, we provided evidence that the microRNA-induced silencing complex (miRISC) core member Ago2 is required for TTP distribution within PBs. Importantly, the cooperation of TTP and Ago2 is a prerequisite for effective ARE-mRNA degradation. Moreover, Dcp1a and Dcp2 act downstream of Ago2 and TTP engaging in ARE-mRNA decay. Finally, we demonstrated that P38 activation represses the interaction between TTP and Ago2 due to TTP phosphorylation, which impairs TTP localization within PBs and ARE-mRNA degradation. Collectively, our study revealed a novel mechanism through which P38 activation repressed the cooperation of TTP with Ago2, thus ensuring that ARE-mRNA does not associate with PBs and remains stable.

scholarly journals mRNA Degradation Rates Are Coupled to Metabolic Status in Mycobacteria

2019 ◽  
Author(s):  
Diego A. Vargas-Blanco ◽  
Ying Zhou ◽  
Luis Gutierrez Zamalloa ◽  
Tim Antonelli ◽  
Scarlet S. Shell
Keyword(s):  
Mrna Stability ◽  
Mrna Degradation ◽  
Metabolic Status ◽  
Basic Knowledge ◽  
Metabolic Adaptation ◽  
Nutrient Deprivation ◽  
Mrna Stabilization ◽  
Growth Status ◽  
Metabolic States ◽  
Multiple Drugs

ABSTRACTThe success ofMycobacterium tuberculosis(Mtb) as a human pathogen is due in part to its ability to survive stress conditions, such as hypoxia or nutrient deprivation, by entering non-growing states. In these low-metabolic states, Mtb can tolerate antibiotics and develop genetically encoded antibiotic resistance, making its metabolic adaptation to stress crucial for survival. Numerous bacteria, including Mtb, have been shown to reduce their rates of mRNA degradation under growth limitation and stress. While the existence of this response appears to be conserved across species, the underlying bacterial mRNA stabilization mechanisms remains unknown. To better understand the biology of non-growing mycobacteria, we sought to identify the mechanisms by which mRNA stabilization occurs using the non-pathogenic modelMycobacterium smegmatis. We found that mRNA half-life was responsive to energy stress, with carbon starvation and hypoxia causing global mRNA stabilization. This global mRNA stabilization was rapidly reversed when hypoxia-adapted cultures were re-exposed to oxygen, even in the absence of new transcription. The stringent response and RNase protein levels did not explain mRNA stabilization, nor did transcript abundance. This led us to hypothesize that metabolic changes during growth cessation impact the activity of degradation proteins, increasing mRNA stability. Indeed, bedaquiline and isoniazid, two drugs with opposing effects on cellular energy status, had opposite effects on mRNA half-lives in growth-arrested cells. Taken together, our results indicate that mRNA stability in mycobacteria is not directly regulated by growth status, but rather seems to be dependent on the status of energy metabolism.IMPORTANCEThe logistics of treating tuberculosis are difficult, requiring multiple drugs for at least six months. Mtb is able to survive within the human host in part by entering non-growing states in which it is metabolically less active, thus rendering it less susceptible to antibiotics. Basic knowledge on how Mtb survives during these low-metabolic states is incomplete, and we postulate that optimized energy resource management –such as transcriptome stabilization—is important for survival. Here we report that mRNA stabilization (increased mRNA half-lives) is a common feature of mycobacteria under stress (e.g. hypoxia and nutrient deprivation) but is not dependent on the mechanisms that have been most often postulated in the literature. Finally, we found that mRNA stability and growth status can be decoupled by a drug that causes growth arrest but increases metabolic activity, indicating that mRNA stability responds to metabolic status rather than to growth rate changes per se. Our findings suggest a need to re-orient the study of global mRNA stabilization to identify novel mechanisms that are presumably responsible.

scholarly journals Stress granules and processing bodies are dynamically linked sites of mRNP remodeling

2005 ◽  
Vol 169 (6) ◽  
pp. 871-884 ◽  
Author(s):  
Nancy Kedersha ◽  
Georg Stoecklin ◽  
Maranatha Ayodele ◽  
Patrick Yacono ◽  
Jens Lykke-Andersen ◽  
...  
Keyword(s):  
Mrna Decay ◽  
Stress Granules ◽  
Mrna Degradation ◽  
Processing Bodies ◽  
Eif2α Phosphorylation ◽  
Protein Components

Stress granules (SGs) are cytoplasmic aggregates of stalled translational preinitiation complexes that accumulate during stress. GW bodies/processing bodies (PBs) are distinct cytoplasmic sites of mRNA degradation. In this study, we show that SGs and PBs are spatially, compositionally, and functionally linked. SGs and PBs are induced by stress, but SG assembly requires eIF2α phosphorylation, whereas PB assembly does not. They are also dispersed by inhibitors of translational elongation and share several protein components, including Fas-activated serine/threonine phosphoprotein, XRN1, eIF4E, and tristetraprolin (TTP). In contrast, eIF3, G3BP, eIF4G, and PABP-1 are restricted to SGs, whereas DCP1a and 2 are confined to PBs. SGs and PBs also can harbor the same species of mRNA and physically associate with one another in vivo, an interaction that is promoted by the related mRNA decay factors TTP and BRF1. We propose that mRNA released from disassembled polysomes is sorted and remodeled at SGs, from which selected transcripts are delivered to PBs for degradation.

When mRNA translation meets decay

2017 ◽  
Vol 45 (2) ◽  
pp. 339-351 ◽  
Author(s):  
Alicia A. Bicknell ◽  
Emiliano P. Ricci
Keyword(s):  
Mrna Stability ◽  
Messenger Rna ◽  
Mrna Decay ◽  
Mrna Translation ◽  
Mrna Degradation ◽  
Mrna Surveillance ◽  
Protein Output

Messenger RNA (mRNA) translation and mRNA degradation are important determinants of protein output, and they are interconnected. Previously, it was thought that translation of an mRNA, as a rule, prevents its degradation. mRNA surveillance mechanisms, which degrade mRNAs as a consequence of their translation, were considered to be exceptions to this rule. Recently, however, it has become clear that many mRNAs are degraded co-translationally, and it has emerged that codon choice, by influencing the rate of ribosome elongation, affects the rate of mRNA decay. In this review, we discuss the links between translation and mRNA stability, with an emphasis on emerging data suggesting that codon optimality may regulate mRNA degradation.

scholarly journals Transient ribosome slowdown at the decoding step triggers mRNA degradation independent of Znf598 in zebrafish

2021 ◽  
Author(s):  
Yuichiro Mishima ◽  
Peixun Han ◽  
Seisuke Kimura ◽  
Shintaro Iwasaki
Keyword(s):  
Mrna Stability ◽  
Mrna Decay ◽  
Expression Patterns ◽  
Mrna Degradation ◽  
Zebrafish Embryos ◽  
Reading Frame ◽  
Genome Wide ◽  
Codon Composition ◽  
Kinetics Of

The control of mRNA stability plays a central role in regulating gene expression patterns. Recent studies have revealed that codon composition in the open reading frame (ORF) determines mRNA stability in multiple organisms. Based on genome-wide correlation approaches, this previously unrecognized role of the genetic code is attributable to the kinetics of the codon-decoding process by the ribosome. However, complementary experimental analysis is required to define the codon effects on mRNA stability apart from the related cotranslational mRNA decay pathways such as those triggered by aberrant ribosome stalls. In the current study, we performed a set of reporter-based analyses to define codon-mediated mRNA decay and ribosome stall-dependent mRNA decay in zebrafish embryos. Our analysis showed that the effect of codons on mRNA stability stems from the decoding process, independent of Znf598 and stall-dependent mRNA decay. We propose that codon-mediated mRNA decay is triggered by transiently slowed ribosomes engaging in a productive translation cycle in zebrafish embryos.

scholarly journals mRNA Degradation Rates Are Coupled to Metabolic Status inMycobacterium smegmatis

mBio ◽  
2019 ◽  
Vol 10 (4) ◽  
Author(s):  
Diego A. Vargas-Blanco ◽  
Ying Zhou ◽  
L. Gregory Zamalloa ◽  
Tim Antonelli ◽  
Scarlet S. Shell
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Mrna Stability ◽  
Mrna Degradation ◽  
Metabolic Status ◽  
Metabolic Adaptation ◽  
Content Type ◽  
Mrna Stabilization ◽  
Growth Status ◽  
Energy Stress ◽  
Multiple Drugs

ABSTRACTThe success ofMycobacterium tuberculosisas a human pathogen is due in part to its ability to survive stress conditions, such as hypoxia or nutrient deprivation, by entering nongrowing states. In these low-metabolism states,M. tuberculosiscan tolerate antibiotics and develop genetically encoded antibiotic resistance, making its metabolic adaptation to stress crucial for survival. Numerous bacteria, includingM. tuberculosis, have been shown to reduce their rates of mRNA degradation under growth limitation and stress. While the existence of this response appears to be conserved across species, the underlying bacterial mRNA stabilization mechanisms remain unknown. To better understand the biology of nongrowing mycobacteria, we sought to identify the mechanistic basis of mRNA stabilization in the nonpathogenic modelMycobacterium smegmatis. We found that mRNA half-life was responsive to energy stress, with carbon starvation and hypoxia causing global mRNA stabilization. This global stabilization was rapidly reversed when hypoxia-adapted cultures were reexposed to oxygen, even in the absence of new transcription. The stringent response and RNase levels did not explain mRNA stabilization, nor did transcript abundance. This led us to hypothesize that metabolic changes during growth cessation impact the activities of degradation proteins, increasing mRNA stability. Indeed, bedaquiline and isoniazid, two drugs with opposing effects on cellular energy status, had opposite effects on mRNA half-lives in growth-arrested cells. Taken together, our results indicate that mRNA stability in mycobacteria is not directly regulated by growth status but rather is dependent on the status of energy metabolism.IMPORTANCEThe logistics of tuberculosis therapy are difficult, requiring multiple drugs for many months.Mycobacterium tuberculosissurvives in part by entering nongrowing states in which it is metabolically less active and thus less susceptible to antibiotics. Basic knowledge on howM. tuberculosissurvives during these low-metabolism states is incomplete, and we hypothesize that optimized energy resource management is important. Here, we report that slowed mRNA turnover is a common feature of mycobacteria under energy stress but is not dependent on the mechanisms that have generally been postulated in the literature. Finally, we found that mRNA stability and growth status can be decoupled by a drug that causes growth arrest but increases metabolic activity, indicating that mRNA stability responds to metabolic status rather than to growth rateper se. Our findings suggest a need to reorient studies of global mRNA stabilization to identify novel mechanisms that are presumably responsible.

scholarly journals Non-invasive measurement of mRNA decay reveals translation initiation as the major determinant of mRNA stability

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Leon Y Chan ◽  
Christopher F Mugler ◽  
Stephanie Heinrich ◽  
Pascal Vallotton ◽  
Karsten Weis
Keyword(s):  
Translation Initiation ◽  
Mrna Stability ◽  
Mrna Decay ◽  
Decay Rates ◽  
Major Determinant ◽  
Processing Bodies ◽  
Non Invasive ◽  
Tightly Coupled ◽  
Mrna Half Life ◽  
Dose Dependent

The cytoplasmic abundance of mRNAs is strictly controlled through a balance of production and degradation. Whereas the control of mRNA synthesis through transcription has been well characterized, less is known about the regulation of mRNA turnover, and a consensus model explaining the wide variations in mRNA decay rates remains elusive. Here, we combine non-invasive transcriptome-wide mRNA production and stability measurements with selective and acute perturbations to demonstrate that mRNA degradation is tightly coupled to the regulation of translation, and that a competition between translation initiation and mRNA decay -but not codon optimality or elongation- is the major determinant of mRNA stability in yeast. Our refined measurements also reveal a remarkably dynamic transcriptome with an average mRNA half-life of only 4.8 min - much shorter than previously thought. Furthermore, global mRNA destabilization by inhibition of translation initiation induces a dose-dependent formation of processing bodies in which mRNAs can decay over time.

scholarly journals A Novel Class of mRNA-containing Cytoplasmic Granules Are Produced in Response to UV-Irradiation

2008 ◽  
Vol 19 (11) ◽  
pp. 4980-4992 ◽  
Author(s):  
Hélène Gaillard ◽  
Andrés Aguilera
Keyword(s):  
Uv Irradiation ◽  
Decay Kinetics ◽  
Processing Bodies ◽  
Mrna Stabilization ◽  
Damage Response ◽  
Rna Damage ◽  
Mrna Granules ◽  
Kinetics Of ◽  
Polyadenylated Mrna

Nucleic acids are substrates for different types of damage, but little is known about the fate of damaged RNAs. We addressed the existence of an RNA-damage response in yeast. The decay kinetics of GAL1p-driven mRNAs revealed a dose-dependent mRNA stabilization upon UV-irradiation that was not observed after heat or saline shocks, or during nitrogen starvation. UV-induced mRNA stabilization did not depend on DNA repair, damage checkpoint or mRNA degradation machineries. Notably, fluorescent in situ hybridization revealed that after UV-irradiation, polyadenylated mRNA accumulated in cytoplasmic foci that increased in size with time. In situ colocalization showed that these foci are not processing-bodies, eIF4E-, eIF4G-, and Pab1-containing bodies, stress granules, autophagy vesicles, or part of the secretory or endocytic pathways. These results point to the existence of a specific eukaryotic RNA-damage response, which leads to new polyadenylated mRNA-containing granules (UV-induced mRNA granules; UVGs). We propose that potentially damaged mRNAs, which may be deleterious to the cell, are temporarily stored in UVG granules to safeguard cell viability.

scholarly journals Scavenger Decapping Activity Facilitates 5′ to 3′ mRNA Decay

2005 ◽  
Vol 25 (22) ◽  
pp. 9764-9772 ◽  
Author(s):  
Hudan Liu ◽  
Megerditch Kiledjian
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Mrna Stability ◽  
Mrna Decay ◽  
Hydrolytic Activity ◽  
Mrna Degradation ◽  
Mrna Turnover ◽  
Threefold Increase ◽  
Mechanistic Analysis ◽  
Decapping Enzyme ◽  
Mrna Half Life

ABSTRACT mRNA degradation occurs through distinct pathways, one primarily from the 5′ end of the mRNA and the second from the 3′ end. Decay from the 3′ end generates the m7GpppN cap dinucleotide, which is subsequently hydrolyzed to m7Gp and ppN in Saccharomyces cerevisiae by a scavenger decapping activity termed Dcs1p. Although Dcs1p functions in the last step of mRNA turnover, we demonstrate that its activity modulates earlier steps of mRNA decay. Disruption of the DCS1 gene manifests a threefold increase of the TIF51A mRNA half-life. Interestingly, the hydrolytic activity of Dcs1p was essential for the altered mRNA turnover, as Dcs1p, but not a catalytically inactive Dcs1p mutant, complemented the increased mRNA stability. Mechanistic analysis revealed that 5′ to 3′ exoribonucleolytic activity was impeded in the dcs1Δ strain, resulting in the accumulation of uncapped mRNA. These data define a new role for the Dcs1p scavenger decapping enzyme and demonstrate a novel mechanism whereby the final step in the 3′ mRNA decay pathway can influence 5′ to 3′ exoribonucleolytic activity.

scholarly journals Non-invasive measurement of mRNA decay reveals translation initiation as the major determinant of mRNA stability

2017 ◽  
Author(s):  
Leon Y Chan ◽  
Christopher F Mugler ◽  
Stephanie Heinrich ◽  
Pascal Vallotton ◽  
Karsten Weis
Keyword(s):  
Translation Initiation ◽  
Mrna Stability ◽  
Mrna Decay ◽  
Decay Rates ◽  
Major Determinant ◽  
Processing Bodies ◽  
Non Invasive ◽  
Tightly Coupled ◽  
Mrna Half Life ◽  
Dose Dependent

AbstractThe cytoplasmic abundance of mRNAs is strictly controlled through a balance of production and degradation. Whereas the control of mRNA synthesis through transcription has been well characterized, less is known about the regulation of mRNA turnover, and a consensus model explaining the wide variations in mRNA decay rates remains elusive. Here, we combine non-invasive transcriptome-wide mRNA production and stability measurements with selective and acute perturbations to demonstrate that mRNA degradation is tightly coupled to the regulation of translation, and that a competition between translation initiation and mRNA decay -but not codon optimality or elongation- is the major determinant of mRNA stability in yeast. Our refined measurements also reveal a remarkably dynamic transcriptome with an average mRNA half-life of only 4.8 minutes - much shorter than previously thought. Furthermore, global mRNA destabilization by inhibition of translation initiation induces a dose-dependent formation of processing bodies in which mRNAs can decay over time.

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