Inhibition of Ribosome Recruitment Induces Stress Granule Formation Independently of Eukaryotic Initiation Factor 2α Phosphorylation

Mazrouï, Rachid; Sukarieh, Rami; Bordeleau, Marie Eve; Kaufman, Randal J.; Northcote, Peter T.; Tanaka, Junichi; Gallouzi, Imed Eddine; Pelletier, Jerry

doi:10.1091/mbc.e06-04-0318

Cited by 287 publications

(325 citation statements)

References 37 publications

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“…Evidently, further studies are required to dissect the function of ATXN2 in translational regulation and how alterations in the intracellular ATXN2 level affect translational processes or potentially mRNA decay. On the one hand, one could speculate that ATXN2 interferes with SG and P-body structures by impairing the correct ribosome assembly granted by RNA helicases, which is required for the induction of SGs (Ripmaster et al, 1992;Mazroui et al, 2006). Moreover, one needs to elucidate in more detail the aspect whether the observed impairment of SG assembly in cells with reduced ATXN2 concentration could potentially arise due to alterations in the intracellular PAPB concentration as well, because PAPB is known to be a translational enhancer.…”

Section: Discussionmentioning

confidence: 99%

“…This causes a decline of the ternary complex eIF2-GTP-tRNA Met and an accumulation of the 48S* preinitiation complex resulting in the disassembly of polysomes and the assembly of SGs (Anderson and Kedersha, 2002a,b;Kedersha and Anderson, 2002). However, recently eIF2␣ phosphorylation-independent pathways, which target translation initiation, have been reported (Dang et al, 2006;Mazroui et al, 2006). Interference with the activity of another initiation factor, eIF4A, induces assembly of SGs.…”

Section: Introductionmentioning

confidence: 99%

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Ataxin-2 Interacts with the DEAD/H-Box RNA Helicase DDX6 and Interferes with P-Bodies and Stress Granules

Nonhoff

Ralser

Welzel

et al. 2007

MBoC

309

320

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Tight control of translation is fundamental for eukaryotic cells, and deregulation of proteins implicated contributes to numerous human diseases. The neurodegenerative disorder spinocerebellar ataxia type 2 is caused by a trinucleotide expansion in the SCA2 gene encoding a lengthened polyglutamine stretch in the gene product ataxin-2, which seems to be implicated in cellular RNA-processing pathways and translational regulation. Here, we substantiate a function of ataxin-2 in such pathways by demonstrating that ataxin-2 interacts with the DEAD/H-box RNA helicase DDX6, a component of P-bodies and stress granules, representing cellular structures of mRNA triage. We discovered that altered ataxin-2 levels interfere with the assembly of stress granules and cellular P-body structures. Moreover, ataxin-2 regulates the intracellular concentration of its interaction partner, the poly(A)-binding protein, another stress granule component and a key factor for translational control. Thus, our data imply that the cellular ataxin-2 concentration is important for the assembly of stress granules and P-bodies, which are main compartments for regulating and controlling mRNA degradation, stability, and translation. INTRODUCTIONAn essential step in the control of global gene expression in eukaryotes is the regulation of mRNA translation and degradation. Shortening of the poly(A) tail is the initial step to trigger mRNA for decay in two major mRNA degradation pathways in eukaryotic cells (Bernstein and Ross, 1989;Peltz et al., 1991;Decker and Parker, 1994;Beelman and Parker, 1995). In one pathway, the deadenylated mRNA is degraded by a cytoplasmic protein complex, the exosome, consisting of a number of exonucleases with 3Ј-5Ј activity (Butler, 2002). In the other pathway, shortening of the poly(A) tail leads to the removal of the cap structure of the mRNA by the decapping proteins DCP1 and DCP2 facilitating 5Ј-3Ј degradation of the mRNA through the exoribonuclease XRN1 (Beelman and Parker, 1995;Butler, 2002). These proteins colocalize in discrete cytoplasmic foci in mammalian cells, termed processing bodies or P-bodies (also known as DCP1-or GW182-bodies), indicating that mRNA decay is restricted to distinct cytoplasmic compartments in mammalian cells (van Dijk et al., 2002;Cougot et al., 2004). The human protein CCR4, which is involved in mRNA deadenylation, the decapping stimulating LSm proteins LSm1-7, the DEAD/Hbox RNA helicase DDX6 (also known as RCK/p54), GW182, and Ge-1 are components of P-bodies (Bouveret et al., 2000;Eystathioy et al., 2002;Ingelfinger et al., 2002; LykkeAndersen, 2002;Cougot et al., 2004;Yu et al., 2005). Moreover, the RNA-associated protein 55, hEDC3, Hedls as well as factors of the RISC complex localize to P-bodies in mammalian cells (Fenger-Gron et al., 2005;Liu et al., 2005;Sen and Blau, 2005;Yang et al., 2006). P-bodies represent dynamic structures that are in an equilibrium with polysomes and contain nontranslating mRNA . Remarkably, recent work demonstrated that mRNA molecules entering P-bodies can a...

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Ataxin-2 Interacts with the DEAD/H-Box RNA Helicase DDX6 and Interferes with P-Bodies and Stress Granules

Nonhoff

Ralser

Welzel

et al. 2007

MBoC

309

320

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“…Cells were fixed, and immunofluorescence was performed as described (19). Anti-HuR monoclonal antibody (3A2) (20), anti-G3BP (Ras GTPase-activating protein SH3 domain-binding protein) polyclonal antibody (23), and Alexa Fluor 488-conjugated secondary antibody (Molecular Probes) were used along with DAPI stain. Images were taken at room temperature with a ϫ63 oil objective using an Axiovert 200M microscope (Carl Zeiss, Inc.) as described previously (6).…”

Section: Methodsmentioning

confidence: 99%

Transportin 2 Regulates Apoptosis through the RNA-binding Protein HuR

Roretz¹,

MacRi²,

Gallouzi

2011

Journal of Biological Chemistry

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In response to severe stress, apoptotic cell death is engaged. Apoptosis is a well orchestrated process that involves the activation and implication of many factors. In this study, we identified a role for the nuclear trafficking factor TRN2 (transportin 2) in cell death. TRN2 is normally responsible for the nuclear import of the RNA-binding protein HuR. During apoptosis, however, HuR accumulates in the cytoplasm. This is due to the caspase-mediated cleavage of the cytoplasmic fraction of HuR. One of the cleavage fragments generated by this processing of HuR interacts with TRN2 and thus blocks the re-import of HuR into the nucleus. This concentrates HuR in the cytoplasm, advancing apoptosis. Therefore, increasing or decreasing the levels of TRN2 has an inverse consequential effect on cell death, demonstrating for the first time the role of a nucleocytoplasmic transport factor in apoptosis.When confronted with stress, eukaryotic cells undergo different responses depending on the severity and duration of the stress (1). Although adaptation and survival are at one end of these responses, cell death can also be the outcome. Apoptotic cell death is a complex pathway involving the activation and cleavage of several proteins, some of the most important of which are cysteine-aspartic proteases (caspases). This family of proteases then cleaves specific substrates, allowing the progression of cell death (2-5). In addition to causing the organized destruction of a cell, caspase-mediated cleavage can also serve to activate target proteins that have important roles in advancing apoptosis themselves. Recently, the RNA-binding protein HuR was identified as one such factor (6). Under normal conditions, HuR is an important regulator of gene expression, controlling the localization, stabilization, and translation of many different mRNAs (7,8). The targets of HuR are involved in many cellular processes, including cell growth, differentiation, and survival and apoptotic cell death. Likewise, the importance of HuR in regulating these processes has been shown, given that its absence or overexpression in different systems can have potent effects on cell physiology (6, 9 -12).The role of HuR as a promoter of cell death was identified when it was found that caspase-3 and caspase-7 cleave HuR in response to lethal stress (6), such as with the use of the apoptotic stimulator drug staurosporine (STS). 4 The cleavage of HuR, occurring at Asp-226 of this protein, yields two cleavage products: HuR-CP1 (26 kDa) and HuR-CP2 (8 kDa). Mutation of this cleavage site prevents apoptosis, whereas providing these two cleavage products can stimulate cell death under nonlethal conditions (13). It was shown that HuR-CP2 helps promote apoptosis by binding to putative HLA-associated protein-I (PHAPI) (6), an activator of apoptosis and a known ligand of full-length HuR. However, the implication of other protein partners has not yet been explored.Intriguingly, prior to its cleavage, HuR, which typically shuttles between the nucleus and the cytoplasm, must ha...

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“…For example, in heat-shocked cells the canonical translation initiation factor eIF4G is bound by Hsp27 and recruited to SGs, thus inactivating the cap binding complex, eIF4F, and inhibiting translation initiation (9). More recently hippuristanol and pateamine A, two compounds that inhibit translation initiation via interaction with eIF4A, another eIF4F component, were found to promote the formation of SGs (5,6,27,29). Notably, SG formation by pateamine A does not require phosphorylation of eIF2␣ (10,29).…”

mentioning

confidence: 99%

“…More recently hippuristanol and pateamine A, two compounds that inhibit translation initiation via interaction with eIF4A, another eIF4F component, were found to promote the formation of SGs (5,6,27,29). Notably, SG formation by pateamine A does not require phosphorylation of eIF2␣ (10,29). Similarly, poliovirus, which inhibits host protein synthesis via cleavage of eIF4G and PABP, also induces SG formation without significant eIF2␣ phosphorylation (29).…”

mentioning

confidence: 99%

Stable Formation of Compositionally Unique Stress Granules in Virus-Infected Cells

Piotrowska

Hansen

Park

et al. 2010

J Virol

106

141

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Stress granules are sites of mRNA storage formed in response to a variety of stresses, including viral infections. Here, the mechanisms and consequences of stress granule formation during poliovirus infection were examined. The results indicate that stress granules containing T-cell-restricted intracellular antigen 1 (TIA-1) and mRNA are stably constituted in infected cells despite lacking intact RasGAP SH3-domain binding protein 1 (G3BP) and eukaryotic initiation factor 4G. Fluorescent in situ hybridization revealed that stress granules in infected cells do not contain significant amounts of viral positive-strand RNA. Infection does not prevent stress granule formation in response to heat shock, indicating that poliovirus does not block de novo stress granule formation. A mutant TIA-1 protein that prevents stress granule formation during oxidative stress also prevents formation in infected cells. However, stress granule formation during infection is more dependent upon ongoing transcription than is formation during oxidative stress or heat shock. Furthermore, Sam68 is recruited to stress granules in infected cells but not to stress granules formed in response to oxidative stress or heat shock. These results demonstrate that stress granule formation in poliovirus-infected cells utilizes a transcription-dependent pathway that results in the appearance of stable, compositionally unique stress granules.

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Inhibition of Ribosome Recruitment Induces Stress Granule Formation Independently of Eukaryotic Initiation Factor 2α Phosphorylation

Cited by 287 publications

References 37 publications

Ataxin-2 Interacts with the DEAD/H-Box RNA Helicase DDX6 and Interferes with P-Bodies and Stress Granules

Ataxin-2 Interacts with the DEAD/H-Box RNA Helicase DDX6 and Interferes with P-Bodies and Stress Granules

Transportin 2 Regulates Apoptosis through the RNA-binding Protein HuR

Stable Formation of Compositionally Unique Stress Granules in Virus-Infected Cells

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